Cytokines in Inflammatory Disease: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects: Pathology
Contributor:
Borna Relja

This review aims to briefly discuss a short list of a broad variety of inflammatory cytokines. Numerous studies have implicated that inflammatory cytokines exert important effects with regard to various inflammatory diseases, yet the reports on their specific roles are not always consistent. They can be used as biomarkers to indicate or monitor disease or its progress, and also may serve as clinically applicable parameters for therapies. Yet, their precise role is not always clearly defined. Thus, in this entry, researchers focus on the existing literature dealing with the biology of cytokines interleukin (IL)-6, IL-1, IL-33, tumor necrosis factor-alpha (TNF-α), IL-10, and IL-8. We will briefly focus on the correlations and role of these inflammatory mediators in the genesis of various inflammatory impacts.

  • cytokine
  • TNF-α
  • IL-6
  • IL-1
  • IL-33
  • IL-10
  • IL-8
  • disease
  • inflammation
  • pathology

1. Introduction

Cytokines are small secreted proteins (<40 kDa), which are produced by nearly every cell to regulate and influence immune response [[1]]. The release of pro-inflammatory cytokines will lead to activation of immune cells and production as well as the release of further cytokines [[2]]. Therefore, in the past when the term “cytokine storm” arose, it explained inflammation as a sudden release of cytokines to upregulate an inflammatory process [[3]]. However, recent research indicates that a simultaneous release of pro- and anti-inflammatory cytokines are mandatory in any immune response [[4]].

Cytokines suffer from a somewhat inconsistent nomenclature; they are referred to as interleukins, chemokines, or growth factors among many other names [[5]]. Cytokines are made up of so-called superfamilies, not necessarily describing common genes, but rather similar structures [[6]]. Furthermore, different cell populations can produce the same cytokine. The effects of cytokines depend on the targeted cell, making them pleiotropic [[5]]. Also, different cytokines may have the same effect and are therefore redundant. They may, however, also have a synergistic effect. Finally, they potentially trigger signaling cascades, giving the smallest amounts of protein the chance to be devastating in consequence [[7]]. A brief overview on various cells expressing different cytokines has been provided in Figure 1.

Ijms 20 06008 g001

Figure 1. A schematic representation of various cells expressing different cytokines. Interleukin (IL), Natural killer cells (NK), Tumor necrosis factor-alpha (TNF-α).

2. Interleukin-6

Interleukin-6 has been shown to play important roles in autoimmune diseases, bacterial infections and metabolic side effects have been observed also [[8]]. It is composed of four α-helices, comparable to other members of the IL-6 family [[8]]. It is translated as a 184 amino acid long protein that undergoes glycosylation and is secreted by T-cells, monocytes, endothelial cells, and fibroblasts [[2]]. Interestingly, IL-6 was first described for its effects on adaptive immunity, like promoting cluster of differentiation (CD)4+ T-cells via IL-21 production, and promoting T-cell differentiation towards T-helper2 cells (Th2) and Th17 cells [[9]]. The very first reference was as a B-cell stimulatory factor by the Kishimoto group in 1986 [[10]]. It has pro- and anti-inflammatory properties, which are described further below. Signaling is achieved via two different mechanisms; one of which is IL-6 binding to its membrane-bound IL-6 receptor (mbIL6R) [[11]]. This complex subsequently recruits two molecules of membrane-bound glycoprotein (gp) 130, a process that leads to downstream signaling via Janus kinases/signal transducer and activator of transcription (STAT) kinases, phosphoinositide 3-kinase (PI3K), and MAP kinases like p38 [[12],[13]]. A major limitation for a sustainable reaction to IL-6 is the availability of the mbIL6R, which is only expressed on certain cell types, while gp130 is found in almost every cell [[14]]. This implies that the systemic influence of IL-6 via classic signaling is rather limited [[2]]. The second mechanism of IL-6 recognition is dependent on the soluble IL-6 receptor (sIL6R), which is expressed via mRNA splicing or proteolysis by a disintegrin and metalloproteinase (ADAM) proteases [[2]]. Interestingly, ADAM proteases cannot be activated only by other cytokines, such as IL-1β or TNF-α [[15]], they can be induced by bacterial toxins as well [[16]]. In the case of sIL6R expression, IL-6 binds to the sIL6R and builds an IL6/sIL6R complex, which in turn activates gp130 on mbIL6R-less cells [[17]]. This process is termed trans-signaling and is responsible for most of IL-6 inflammation-inducing capabilities [[8]]. Currently, similar to the C-reactive protein (CRP), IL-6 is used to “monitor” inflammation levels in patients with cancer, infection, or autoimmune diseases [[18],[19]]. The reason for using IL-6 as a biomarker is its central role in activating and maintaining the inflammatory response. For instance, the clinical quantification of IL-6 is a strong predictor for mortality in pancreatic and cardiovascular disease [[20],[21]]. However, unfortunately, its anti-inflammatory properties, further described below, are so far neglected in clinical practice. While early inflammation is dominated by neutrophils, later states of inflammation are dominated by monocytes. IL-6 is essential in this so-called leukocyte switch [[22]]. Subsequently, it reduces neutrophil recruitment via suppression of chemokines attracting polymorphonuclear leukocytes (PMNL), like the chemokine (C-X-C motif) ligand (CXCL)1 and CXCL8 (IL-8), while upregulating monocyte attracting chemokines CC-chemokine ligand (CCL)2/monocyte chemotactic protein (MCP)-1 and CCL8/MCP-2 in vitro and in vivo [[22]]. Furthermore, cell adhesion molecules like vascular cell adhesion molecule (VCAM) 1, intercellular cell adhesion molecules (ICAM) and E-selectin are upregulated by IL-6 in a fever range mice model [[23]]. In models with gp130 knockout mice, the ability of IL-6 to enhance macrophage-colony stimulating factor (M-CSF) receptor expression, thereby accelerating monocyte differentiation to macrophages, was linked to its gp130 MAP kinase pathway [[24]]. In a Staphylococcus epidermidis induced peritoneal inflammation mice model, IL-6 was mandatory for the recruitment of T-cells [[25]]. Interestingly, classic signaling of IL-6 is needed for regenerative and protective processes in the body. For instance, in inflammatory disease mice models and diverse knockout mice models, IL-6 was essential to liver regeneration, gut barrier repair, and suppression of inflammation in the kidney and pancreas [[26],[27],[28]].

In clinical practice, the first association of IL-6 with cardiovascular disease and cancer was found in 1990 [[29]]. Enhanced levels of IL-6 were found in three patients with cardiac myxomas and removal of the tumor abolished the IL-6 levels [[29]]. In fact, increased pretreatment levels of IL-6 can be a predictor of survival in head and neck cancer [[30]]. Yet, it often remains unclear if IL-6 is only correlative to cancer or rather essential in cancer genesis. A study by Zhang et al. demonstrated that escalated levels of IL-6R in sera from nasopharyngeal carcinoma (NPC) patients are not just correlative [[31]]. The cytokine serves as a catalyst for the malignant transformation of Epstein–Barr infected nasopharyngeal cells to cancerous cells in vitro via STAT kinases [[31]].

Osteoporosis is a common disease in the aging population and studies have shown that IL-6 is potentially implicated in its pathogenesis [[32]]. IL-6 stimulates bone resorption. Several studies have examined the association between IL-6 gene polymorphisms and bone mineral density [[32],[33],[34]].

Another prominent use of IL-6 as a biomarker is in sepsis or after major trauma. Studies in the nineties demonstrated 1000-fold increased IL-6 levels in septic patients and correlation with the gravity of organ failure [[35]]. Likewise, the detection of IL-6 is correlative to invasiveness and duration of surgery [[36]]. Levels of IL-6 after trauma usually do not reach those of septic patients [[37]]. Unlike CRP, IL-6 can also help to distinguish infection from fever of unknown origin in pediatric practice [[38]]. Several studies confirm a predictive value of IL-6 for mortality and organ dysfunction in sepsis or after major trauma [[39],[40]]. While IL-6 has undoubted prognostic value in early inflammation, clinical use has not seen any breakthroughs. Many physicians prefer a combination of clinical presentation, white blood count, CRP levels, and fever measurement over the expensive IL-6 determination [[37]].

3. Interleukin 1 Family

Interleukin-1α and IL-1β were the first cytokines to be discovered in 1974 by Charles A. Dinarello, and since then, they have been greatly studied [56]. In this review, we will focus on the following members of the IL-1 family: IL-1α, IL-1β, and IL-33.

Interleukin-1α and IL-1β are encoded by different genes but can be bound by the same IL-1 receptor (IL-1R) [[41]]. While IL-1α has a higher affinity for IL1-R1, IL-1β has a higher affinity for the soluble IL-1R2 [[42]]. Both are translated as 31 kDa precursor protein and cleaved into smaller 17 kDa forms, albeit with different amino acid sequences [[43]].

The IL-1α precursor is usually found in intracellular space, as well as constitutively in many cell types including hepatocytes, nephrotic epithelium, endothelium, and epithelial cells of the gastro-digestive tract [[44]].

Even in cases of severe infection, relatively low concentrations are found in extracellular space [[45]]. Upon stimuli such as oxidative stress or cytokine exposure, e.g., other IL-1 family cytokines, the expression of the IL-1α mRNA is inducible [[46]]. Nevertheless, it is not clear if post-translational modifications are needed for IL-1α to become active. In contrast to IL-1β and IL-33, the precursor form of IL-1α and recombinant human mature IL-1α have the same biological activity in inducing IL-6 and TNF-α in human peripheral blood mononuclear cells (PBMCs) and lung cancer cells [[47]]. Nevertheless, the secretion of IL-1α protein is well regulated. During apoptosis, cytosolic IL-1α translocates to the nucleus and binds firmly to chromatin [[48]], while during necrosis, it becomes released from the nucleus into the local tissue upon degradation of the cell membrane [[48]]. This exemplifies the properties of IL-1α as an alarmin. Whereas the release of IL-1α during the process of necrosis is explained by the loss of plasma membrane stability, the leakage of IL-1α in “healthy” cells is induced via pyroptosis [[49]]. This is a process of the so-called inflammation-induced apoptosis, which leads to enhanced cell membrane permeability through the formation of an inflammasome complex in an, e.g., caspase-1-dependent mechanism [[49]]. Caspase-1 knock-out mice displayed significantly less IL-1α protein release by monocytes upon their stimulation with LPS and ATP as compared to the wild-type mice [[50]]. The soluble decoy receptor IL-1R2 functions as a receptor in plasma, and limits spreading of IL-1α, thereby reducing its signaling and restraining inflammation [[51]]. Another unique trait among the IL-1 family is that the pro-IL-1α in its full length is implemented in the cell membrane in case of inflammation, and can operate as a fully active membrane-bound cytokine [[42]].

The primary sources of IL-1β are hematopoietic cells like monocytes, macrophages such as microglia or Kupffer cells and dendritic cells upon activation of PRR by PAMP or DAMP [[6]]. Furthermore, alpha cells of pancreas secrete IL-1β, and this can be studied in diabetic and obese patients [[52]]. Recent trials imply the contribution of epithelium and endothelial IL-1β to cardiovascular disease [[53]].

In contrast to IL-1α, IL-1β precursor is not biologically active, as its activation requires a proteolytic step by the IL-1β converting enzyme, e.g., caspase-1 within the multiprotein inflammasome complex [[54]]. Upon activation of myeloid differentiation primary response (MyD)88 in case of hypoxia, complement activation, or even IL-1β itself, pro-IL-1β mRNA is induced [[6],[55]]. The translation occurs in the cytosol, however, it is discussed if a second signal is required for pro-IL-1β to be cleaved to IL-1β, and thereby activated [[56]]. Second signals can include DAMP or alarmin molecules, such as ATP, which binds to P2 × 7 receptors, thereby providing a signal to open potassium channels lowering intracellular potassium levels [[57]]. In consequence, the formation of NOD-like receptor (NLR) sensor molecule, such as NOD-, leucine-rich repeat (LRR)- and pyrin domaine-containing protein (NLRP)3 [[58]], and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) to the inflammasome complex occurs [[6]]. As a result, pro-caspase-1 is activated into caspase-1 and cleaves, e.g., pro-IL-1β or pro-IL-18 cytokine precursors to their active forms, thereby initiating or enhancing the pro-inflammatory response [[59]].

In the last decades huge advances have been made in understanding the role of inflammasomes in the pathogenesis of infectious, autoinflammatory and autoimmune diseases. Familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disorder (NOMID, also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome) have been shown to be caused by gain of function mutations in the NLPR3 gene encoding for cryopyrin, leading to increased caspase-1 and IL-1β activity [[60],[61],[62],[63]]. Due to their similar etiology these diseases are today recognized as a group of diseases named pryopyrin-associated periodic syndrome (CAPS). Current treatment of CAPS is successfully and safely based upon three different medications named rilonacept (captures IL-1β as a decoy receptor), anakinra (IL-1R antagonist), and canakinumab (monoclonal antibody against IL-1β) [[64],[65]]. Regarding the role of NRLP3 in the development of atherosclerosis Duewell et al. reported decreased development of atherosclerotic lesions in mice lacking inflammasome related molecules NLRP3, ASC or IL-1α/β and showed that cholesterol crystals as a possible DAMP strongly activated NLRP3 inflammasomes in macrophages [[66]]. Further studies in similar mouse models as well showed decreased severity of atherosclerosis in mice lacking NLRP3, caspase-1 or IL-1β [[67],[68],[69]], while in another study NLRP3 inflammasomes were not critically implicated in atherosclerosis progression [[70]]. Furthermore, the NLPR3 inflammasome is activated by oxidized low-density lipoprotein (LDL) and high levels of triglyceride, both being major risk factors for atherosclerosis [[66],[71],[72]].

The role of inflammasomes in the pathogenesis of rheumatoid arthritis has been studied extensively in the past decades in humans as well as in specific animal models. Guo et al. recently showed that the NLRP3 inflammasome was highly activated in synovia from patients with rheumatoid arthritis and in an animal model with collagen-induced arthritis (CIA) in mice [[73]]. Furthermore, treatment with MCC950, a selective NLRP3 inhibitor, in the animal model resulted in significantly less severe joints inflammation and bone destruction [[73]]. In a study by Ippagunta et al. the authors investigated the role of different components of the NLRP3 inflammasome and showed that NLRP3(–/–) and caspase-1(–/–) mice were predisposed to collagen-induced arthritis while ASC(–/–) mice were protected from arthritis [[74]]. Another study by Joosten et al. investigated the role of caspase-1, the downstream effector of inflammasomes, in the development of rheumatoid arthritis and obtained conflictive results showing no effect of caspase 1 deficiency in a model of acute (neutrophil-dominated) arthritis but reduced joint inflammation and cartilage destruction in a mouse model of chronic arthritis [[75]]. The crucial role of NRP3 inflammasomes in the development of rheumatoid arthritis was investigated by Vande Walle et al. showing that knock out of A20, a rheumatoid arthritis susceptibility gene, in mice led to increased expression of NLRP3 and pro-IL-1β genes and resulted in induction of NLRP3 inflammasome-mediated caspase-1 activation, pyroptosis, and IL-1β secretion [[76]].

Furthermore, deletion of NLRP3, caspase-1 and the interleukin-1 receptor markedly protected against rheumatoid-arthritis-associated inflammation and cartilage destruction in A20myel-KO mice and the authors depicted A20 as a novel negative regulator of NLRP3 inflammasome activation in rheumatoid arthritis [[76]]. Patients with active rheumatoid arthritis have higher intracellular levels of NLRP3 inflammasome components (including NLRP3, ASC, active caspase-1, and pro-IL-1β) as well as increased secretion of IL-1β [[77]] and monocytes from patients with rheumatoid arthritis show increased IL-1β production mediated by activation of NLRP3 inflammasome [[78]]. Shin et al. investigated the role of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) as a treatment for rheumatoid arthritis in mice with collagen-induced arthritis (CIA) and observed a reduced severity of CIA mediated by a downregulation of the NRLP3 inflammasome [[79]].

While a huge part of current and past research focused on NLRP3 inflammasomes, it could be shown that the G allele of a polymorphism (rs878329) in the NLRP1 promoter in the Chinese population up-regulates gene transcription and puts patients at risk for developing rheumatoid arthritis [[80]]. Treatment of CIA mice with BVT-2733, a selective inhibitor of 11β-hydroxysteroid dehydrogenase 1, attenuated arthritis severity by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways [[81]]. Investigation of treatment with P2X4 antisense oligonucleotide (asODN) in the same CIA model indicated significantly reduced synovial inflammation and joint destruction by inhibition of NRLP1 inflammasome as the underlying mechanism [[82]].

Recently, mutations in the NLRP1 gene were shown to cause a novel autoinflammatory disorder that the authors proposed to call NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis) which causes arthritis and dyskeratosis [[83]]. Unfortunately, there are only a few studies analyzing the importance of inflammasomes in the pathogenesis of osteoporosis. IL-18BP, the natural antagonist of proinflammatory IL-18, was shown to be reduced in osteoporotic women [[84]]. Animal experiments from the same group showed that mIL-18BPd enhances osteoblast differentiation and inhibits the activation of NLRP3 inflammasome and caspase-1 in vitro [[84]]. In vivo mIL-18BPd treatment restored trabecular microarchitecture, preserved cortical bone parameters and reduced osteoclastogenesis [[84]].

Xu et al. investigated melatonin treatment in ovariectomized C57BL/6J mice and demonstrated that melatonin improved osteoporosis and impaired osteogenic differentiation potential by suppressing activation of the NLRP3 inflammasome via mediating the wingless-related integration site (Wnt)/β-catenin pathway [[85]]. Humanized mice carrying an NLRP3 mutation (D305N/D305N mice) developed arthritis and osteoporosis shown by increased radiolucency and thinner cortices in all bones of the lower hindlimb compared to control animals [[86]]. Kim et al. investigated auranofin, a gold-based compound approved in 1975 for the treatment of rheumatic diseases and found that auranofin suppresses inflammasome mediated IL-1β secretion in mouse bone marrow-derived macrophages (BMDMs) and J774.A1 cells [102]. Furthermore, administration of auranofin in ovariectomized mice led to recovery of bone mass [[87]].

In in vitro studies with human mesenchymal stem cells (MSCs), activation of NLRP3 inflammasome by lipopolysaccharide and palmitic acid (LPS/PA) treatment led to increased adipogenesis of MSCs and suppressed osteogenesis [[88]]. The role of inflammasomes in the pathogenesis of age-related diseases especially of the eyes (e.g., glaucoma or age-related macula degeneration) has been extensively studied in the past years and is reviewed profoundly elsewhere. In a mouse model of acute glaucoma the role of HMGB1 has been investigated and it was shown that HMGB1 activates the canonical NLRP3 and non-canonical caspase-8 inflammasomes and production of IL-1β during acute glaucoma development [[89]]. In a previous study by the same group was shown that inhibition of caspase-8 activation significantly attenuates retinal ganglion cell death by down-regulating the activation of NLRP1 and NLRP3 [[90]].

Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide [[91]] and huge progress has been made in the last decades to understand the role of inflammasomes in the pathogenesis of the disease. Doyle et al. showed that drusen, which are the major pathological hallmark of AMD, isolated from donor AMD eyes activate the NLRP3 inflammasome leading to secretion of IL-1β and IL-18 [[92]]. Interestingly in a mouse model of wet AMD in NLRP3(–/–) mice laser-induced choroidal neovascularization (CNV) was exacerbated so the authors concluded that NLRP3 and IL-18 might have a protective role in the progression of AMD [[92]]. The latest findings with regard to the connection between inflammasomes and AMD are thoroughly reviewed elsewhere [[93],[94]]. Trauma is one of the leading causes for death worldwide and although it is indisputable that trauma-injury is closely associated with inflammasomes, there is no clear hypothesis whether the activation of inflammasomes is harmful or beneficial after trauma.

In an ex vivo in vitro experiment with LPS stimulation of CD14+-isolated monocytes from trauma patients (TP), gene expression of NLRP1 was markedly reduced compared to healthy controls [[95]]. Furthermore, transfected monocytes from TP, which expressed the lacking components, were recovered in their LPS-induced IL-1β release, and thus, the authors concluded that lacking NLRP1 is responsible for the suppressed monocyte activity after trauma [[95]]. NLRP1 has been shown to be an important component of the innate central nervous system inflammatory response after traumatic brain injury (TBI) as its neutralization reduced the innate immune response and improved histopathology after TBI in a mouse model [[96]]. Furthermore, the NLRP1 inflammasome was found to cause lung injury in a mouse model while lung damage was rather caused by pyroptosis of resident lung macrophages and not by caspase-1 or IL-1β [[97]]. NLRP1–/– mice were protected from these detrimental effects, indicating the pivotal role of NLRP1 in lung injury [[97]].

Recent investigations regarding inflammasome proteins as potential biomarker for TBI determined that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in serum and cerebral spinal fluid (CSF) as well as IL-18 in CSF are promising biomarkers of TBI pathology [[98]]. Moreover, higher protein levels of ASC were consistent with poorer outcomes after TBI [[98]]. Zhang et al. reported that genetic variations in the NLRP3-gene predict the development of sepsis and multi organ dysfunction syndrome (MODS) in trauma patients [[99]]. Continuous injury caused by mechanical ventilation, which is common in severely injured trauma patients, is supposed to be mediated by an increase in serum levels of DAMP (e.g., ATP or reactive oxygen species (ROS)), followed by activation of the NLRP3 inflammasome [[100],[101],[102]]. To investigate the underlying mechanism of why up to 30% of patients with TBI develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), Kerr et al. studied extracellular vesicle (EV)-mediated inflammasome signaling in male C57BL/6 mice [[103]].

TBI leads to the release of EVs containing inflammasome proteins into serum that target the lung to cause ALI and administration of a blocker of EV uptake (enoxaparin) or monoclonal antibody against ASC improved ALI scores, thus, the authors concluded that neural-respiratory-inflammasome axis is an important part of the innate inflammatory response in lung pathology after TBI [[103]]. In an animal model of TBI, resveratrol was indicated to attenuate the inflammatory response and relieve TBI by reducing ROS production and inhibiting NLRP3 activation [[104]]. In burn-injured mice blocking of caspase-1, the downstream effectors of inflammasomes, caused significantly higher mortality, thus, Osuka et al. concluded that inflammasome activation plays a protective role in the host response to severe injury [[105]]. In contrast, treatment with MCC950, an inhibitor of the NLRP3 inflammasome, led to a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions in a mouse model with TBI [[106]].

Inhibition of the NLRP3 inflammasome by treatment with BAY 11-7082 or A438079 alleviated the severity of spinal cord damage and improved neurological recovery after in a mouse model of spinal cord injury [[107]]. Another recent study showed protective effects in cholestatic liver injury and liver fibrosis by blocking NLRP3 inflammasome activation by treatment with MCC950 [[108]]. As these are still preclinical studies the value for clinical treatment has to be investigated intensively. In a rat model of subarachnoid hemorrhage minocycline protected against NLRP3 inflammasome-induced inflammation and p53-associated apoptosis, and therefore, the authors concluded that treatment with minocycline treatment may exhibit important clinical potentials in the management of subarachnoid hemorrhage [[109]]. Denes et al. investigated the role of NLRC4 and AIM2 in a rodent model of stroke and showed that that ischemic brain injury has been reduced in ASC−/− and NLRC4−/− mice without seeing such protective effects, in mice deficient for NLRP3 [[110]]. Although huge advances have already been made in recent decades, the specific role of the inflammasome in the development of several diseases and therapeutic options still has to be investigated intensively in future.

As the biological activities of both IL-1α and IL-1β are rather similar, this review will refer to them as IL-1 in the following paragraph. Models with IL-1 deficient mice displayed no difference to control mice in terms of growth, homeostasis or fertility, however, they were rather prone to bacterial, mycotic and protozoa infections [[6],[111]]. The ability of IL-1 to stimulate synthesis of inducible nitric oxide synthase (iNOS), Cyclooxygenase (COX)-2 and phospholipase (PL)A2 results in enhanced production of nitric oxide (NO), platelet activating factor as well as prostaglandin (PG)E2 in ex vivo in vitro analyses of chondrocytes from patients with osteoarthritis [[112]]. Accordingly, the patients in an inflammatory state experienced vasodilation and hypotension, fever and heightened pain sensitivity [[113]]. To raise systemic dissemination and infiltration of immune cells, chemokine production is upregulated as well as expression of ICAM-1 and VCAM-1 in mesenchymal stem cell models in vitro [[114]].

Another trait is the augmented permeability of the intestinal barrier and a blood-brain barrier to simplify neutrophil recruitment in these compartments as observed in in vitro models with Caco2-monolayers [[115]]. A mice model with LPS challenge revealed the angiogenic potential of IL-1 to contribute to blood vessel formation under hypoxic conditions [[116]]. However, modulation of lymphocytic response like B-cell proliferation is strictly seen as an effect of IL-6 that is inducted by IL-1 as seen in an animal model with either IL-6 or IL-1 knockout mice [[117]]. In fact, 1 ng/kg bodyweight IL-1 is enough to ensure high systemic levels of IL-6 in mice [[6]]. Thus, this stresses the important role of IL-1 in disease rather than in healthy individuals. The diagnostic value of IL-1 is rather limited due to its half-life of around 10 min [[118]]. However, some clinical studies determined IL-1 levels in sera via ELISA. One of those is a work by a Turkish group in neonatal sepsis (n = 50) that revealed significantly enhanced levels of IL-1 in septic patients [[119]]. Another study displayed significant levels of IL-1 in sera of malaria patients compared to control in a cohort of 60 patients [[120]]. Interestingly, IL1-Ra was not only significantly increased in patients with septic shock on admission day and day 28 but was also a predictor of mortality [[121]].

Emerging evidence highlights the role of these inflammatory cytokines in the regulation of bone homeostasis. Chronic inflammation is often characterized by an imbalance between bone formation and bone resorption. Here, a net prevalence of osteoclastogenesis has been described, which is an important determinant of bone loss in rheumatic diseases [[122]]. Yet, the totality of evidence is limited and provides no clear indication of which cytokine is the most important for bone biology. The link between osteoclasts and pro-inflammatory cytokines, especially IL-1, provides an explanation for the association between inflammation and osteoporosis. For inflammatory diseases, bisphosphonates may be chosen as therapy, however specific medications such as denosumab, IL-1 receptor antagonists, or TNF-α antibodies are targeted treatment strategies for osteoporosis secondary to inflammation [[123]].

In a meta-analysis to examine the efficacy and safety of denosumab in postmenopausal women with osteoporosis by Gu et al., adverse events between verum and placebo group were similar (pooled odds ratio  =  1.04, p  =  0.625) [[124]]. In a large cohort study Choi et al. observed comparable clinical safety and effectiveness with regard to the risk of serious infection, cardiovascular disease, and osteoporosis fracture within 365 days after initiation of medications between denosumab and zolendronic acid (an established standard of therapy) [[125]]. Kullenberg et al. investigated the safety of treatment with anakinra, a IL-1 receptor antagonist, in 43 patients for up to five years and observed 24 serious AEs (SAEs), all of which resolved during the study period, in 14 patients with the most common SAEs being infections such as pneumonia and gastroenteritis [141]. The authors concluded treatment with anakinra of patients with severe CAPS for up to 5 years was safe and well tolerated, both in pediatric and adult patients [[126]]. To assess the safety of treatment with TNF-α antibodies is difficult due to the many different antibodies which are authorized for treatment of e.g., rheumatoid arthritis. Hernández et al. observed a reasonable safety profile for TNF-α antibodies and argue that the benefits far outweigh the possible risk of adverse events [[127]]. There are several studies and meta-analysis dealing with these TNF-α antibodies and which are extensively reviewed elsewhere.

Interleukin-33 is the newest member of the IL-1 family and located on chromosome 9 [[128]]. Human IL-33 is located in the cell nucleus but is also found outside the cell as an alarmin [[129]]. Furthermore, it is synthesized as a 31 kDa protein [[128]]. The main sources of IL-33 are non-hematopoietic cells such as endothelial and epithelial cells [[130]]. IL-33 is a ligand to orphan receptor ST2 [[131]] of the TLR/IL1R superfamily of receptors, thereby potentially activating canonical NF-κB pathway via MyD88 [[132]]. Nevertheless, it was first described as a nuclear factor from high endothelial venules (NF-HEV) [[133]]. The name accurately describes its properties being both, a membrane receptor ligand and a nuclear factor for transcription [[129]]. Furthermore, distinct to other members of the IL-1 family such as IL-1β or IL-18, n-terminal end of IL-33 does not necessitate processing to be active [[128]]. Nonetheless, IL-33 lacks a secretory sequence for conventional pathways to be secreted into extracellular space [[134]]. One would suspect necrosis as a primary form causing its release, however, in vivo and in vitro models indicate that living cells secrete IL-33 as well [[135]]. Recent research of inflammation models like post-viral mice with chronic lung disease and in patients with chronic lung disease indicate that extracellular ATP may play a role in IL-33 expression [[136]]. Ex vivo analysis of airway basal cells of the mice revealed significant IL-33 secretion upon ATP exposure [[136]].

Its biological impact is associated with the type 2 immune response, mainly reliant on the activation of Th2 cells, eosinophils, mast cells, basophils and group 2 innate lymphoid cells (ILC-2) [[128],[134]]. These cell populations express ST2 and show the importance of IL-33 in allergic and autoimmune disease [[130],[137]]. For instance, chronic exposure of cigarette smoke to mice leads to enhanced systemic IL-33 levels [[138]]. Additionally, IL-33 skews T-cells toward Th2 differentiation, and high concentrations of this cytokine act as a chemoattractant for Th2 cells [[139],[140]]. There is growing evidence that cells such as Th1, neutrophils, macrophages and natural killer cells (NK) express little ST2 in physiological conditions [[141]]. Yet, after priming with IL-12 in case of infection, the expression of the ST2 receptor, and thus susceptibility for IL-33 is highly increased [[128],[142]]. This is emphasized by the ability of IL-33 to induce IFN-γ protein expression by aforementioned cells [[143]]. Subsequently, this mechanism is protective for the host as Bonilla et al. showed that IL-33 is needed for antiviral responses of CD8 cells in mice [[144]].

As briefly described above, there are several cytokines involved in the pathogenesis of osteoporosis. Yet, the involvement of IL-33 in osteoporotic patients has been studied well. Recently, IL-33 levels in the serum of 50 postmenopausal osteoporotic patients and 28 healthy postmenopausal control women were measured [[145]]. In postmenopausal osteoporotic women IL-33 was lower compared to controls and positively correlated respectively with serum levels of parathyroid hormone, while an inverse correlation was observed between IL-33 and C-terminal telopeptide of type 1 collagen levels. The authors suggest that IL-33 may represent an important bone-protecting cytokine which may hide therapeutic benefits for treating bone resorption.

4. Tumor Necrosis Factor-alpha

Tumor necrosis factor-alpha was first described in 1975 by Carswell et al. for its cytotoxic activity to tumor cells via immune cells and thus was named TNF [[146]]. It is expressed as a type II transmembrane protein (mbTNFα) but can be cut to its soluble form (sTNFα) with increased biological activity [[147]]. The enzyme responsible for its cutting is TNF converting enzyme (TACE) or ADAM17 [[148]]. The membrane-bound mbTNFα has a 233 amino acid sequence, weighs 26 kDa and forms homotrimers [[149]]. This mbTNFα complex is cut to 51 kDa by TACE [[150]]. The main supply of TNF-α are macrophages and T-cells, yet many other cells such as B-cells, neutrophils, and endothelial cells have been described to produce TNF-α [[150]]. Targets for TNF-α include two type I transmembrane receptors, TNF receptor I (TNFR-I or CD120a) and TNF receptor II (TNFR-II or CD120b) [[151]]. Whereas TFNR-I is expressed on every cell except erythrocytes, TNFR-II is found only on endothelial and immune cells and can be activated by mbTNF [[152]].

The functional relevance is broad, and one prominent trait is the mediation of cell survival and pro-inflammatory response by TNFR-I via NF-κB and activator protein (AP)-1 [[153]]. Additionally, TNF-α instigates signaling pathways of cell death via Fas and Caspases [[147],[152]]. For instance, this was demonstrated in in vitro ex vivo analyses of hematopoietic stem and progenitor cells of TNF-α knockout mice [[154]]. In a clinical study including 34 patients with at least 20% of total burn surface area, it was shown that systemic TNF levels correlated with burn severity and predicted a susceptibility to infection [[155]]. Just like in the case of IL-1, the determination of TNF-α levels can be very tricky because of a half-life of only 14 min [[118]]. Therefore, fast acquisition of blood samples to quantify TNF-α is imperative to use it as a potential biomarker. A German group reported significant levels of TNF-α and sTNF-α in blood samples taken 4, 12, and 24 h after admission to hospital as compared to control in patients with traumatic injury (n = 47) [[156]].

Adjacent to triggering the release of acute phase proteins after trauma, burns or infarction inter alia, TNF-α can initiate blood clotting [[157]]. Clinically, this can lead to a disseminated intravascular coagulation in case of severe inflammation like sepsis, cutting vital organs from blood perfusion, and thus driving them to failure [[150],[152]]. To ensure necessary infiltration of immune cells to the local site of inflammation, e.g., in case of traumatic injury, vasodilation is essential [[158]]. Potent vasodilators are NO and prostaglandins like prostaglandin (PG)I2 or PGE2, which can be induced by TNF-α via iNOS and COX-2 upregulation [[159]]. In addition, expressions of adhesion molecules like E-selectin or ICAM-1 are upregulated by TNF-α aiding extravasation of monocytes and neutrophils in an endothelial cell model [[160]]. Yet, to effectively abolish bacterial infection, PMNLs use ROS as a means to destruct pathogens [[161]]. The essential protein for production of ROS is the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase [176]. In an endothelial cell model, TNF-α was shown to be a potent inductor of NADPH oxidase (NOX) proteins gp91phox, p22phox and p67phox that are needed for NADPH oxidase activation [[162]].

In the late eighties, the first in vivo studies with TNF-α antagonists were carried out showing promising results. In 1985, Beutler et al. showed that mice treated with anti-TNF-α serum had higher survival rates after LPS administration compared to control group mice [[163]]. Shortly after, Tracey et al. infused female baboons with anti-TNF-α antibodies, and injected them with a lethal dose of Escherichia coli (LD100) [[158]]. Baboons with antibodies were protected against shock, vital organ dysfunction, persistent stress hormone release and death as compared to control animals [[158]]. Yet, other studies with TNF-α knockout mice have provided evidence that, while animals may be protected against shock, they were far more susceptible to bacterial challenge [[164]]. Subsequent clinical studies with septic and shock patients have uncovered that there was no significant benefit for critically ill and septic patients treated with experimental TNF-α and sTNF-α antagonists [[165]]. It has to be considered that the used substances were not the known modern TNF-α antagonists. However, TNF-α antagonists such as etanercept, infliximab, or adalimumab proved to be a highly effective treatment for auto-inflammatory diseases like psoriasis, Crohn’s disease, or rheumatoid arthritis [[163]].

The role of the immune system in the onset of osteoporosis, a serious worldwide public health concern, is an area of current research. In a panel including 10 cytokines obtained from postmenopausal women, with either normal or low bone mineral density IL-23, IL-12, IL-4, IL-6, and also TNF-α levels were the most important differentiating cytokines [[166]]. However, no significant difference between the osteopenic and osteoporotic groups were found [[166]]. In general TNF-α suppresses osteoblasts activity at some stages of differentiation and stimulates osteoclast proliferation and differentiation [[167]]. Similar to IL-6, TNF-α can regulate bone metabolism through the endocrine way [[168]]. In a retrospective cohort analysis including a total of 199 rheumatoid arthritis patients, who were newly diagnosed with osteoporosis and receiving bisphosphonate changes in bone mineral density after one year were compared between patients treated with and without TNF inhibitors [[169]]. The therapy did not influence bone mineral density improvement in rheumatoid arthritis patients with osteoporosis receiving bisphosphonate [[169]]. However, although this data suggested that TNF inhibition cannot be considered as a preferred therapeutic option for increasing bone mineral density, conflictive findings have been reported showing that the use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control [[170]]. Recently it was shown that altered T-cell activity and a different composition such as the CD14+CD16+ vs. CD14+CD16- monocytes and priming of osteoclast precursors with increased macrophage colony-stimulating factor (M-CSF), receptor activator of NF-κB ligand (RANKL), and TNF-α levels in peripheral blood play a role in increased osteoclast formation and activity [[171]]. In summary, these findings may help the development of cytokine therapies for osteoporosis, and propose that the use of certain cytokine profiles as biomarkers for osteoporosis risk factors, may quantify the progress of therapies.

5. Interleukin-10

In 1989, IL-10 was first described by Fiorentino et al. as a cytokine synthesis inhibitory factor (CSIF) [[172]]. It is made up as a homodimer with each unit having a 178 amino acid sequence [[173]]. Interestingly, IL-10 is one of few anti-inflammatory cytokines next to IL-2, TGF, and the more recently discovered IL-25, IL-35, and IL-37 [[174]].

Biologically, IL-10 is usually found as a dimer and shares some structural and functional properties of interferon (IFN)-γ [[175]]. It is produced by almost all leukocytes including macrophages, dendritic cells, neutrophils, NK cells, B-cells, and CD8+ T-cells, however, CD4+ T-cells are the major producers [[4],[176]]. For instance, FoxP3+ regulatory CD4+ T-cells (Tregs, thymus, and periphery-derived) and Foxp3- regulatory CD4+ T-cells (Tr1 cells) attenuate T-cells and Th17 cell response in particular via IL-10 [[4],[177]]. This review, however, will focus on the contribution of the cells of innate immunity.

Interestingly, some viruses like Epstein–Barr or Human Cytomegalovirus among others produce IL-10 homologs, which are almost identical to human IL-10 [[178]]. The receptor responsible for downstream signaling of IL-10 is the IL-10 receptor (IL10R), which is made up of dimers IL10R1 and IL10R2 [[179]]. The former is an IL-10 specific receptor and the primary binding site for IL-10, while the latter enhances the affinity of IL-10 to bind to IL10R1 [[179]]. In fact, IL10R2 cannot associate with IL-10 independently, and is expressed on many tissue cells [[180]], while IL10R1 is mostly expressed on immune cells such as T-cells [[177]], neutrophils upon LPS administration in vitro [[181]] or monocytes in a LPS endotoxemia mouse model [[182]. Nevertheless, IL10R2 is a co-ligand to many other molecules like IL-22, IL-26, or IL-29, thereby playing a role in various biological pathways [[178],[183]].

Downstream mediators of the IL-10 receptor are mainly STAT molecules and Janus Kinases (JAK) [[184]]. As a matter of fact, IL-10R1 is associated with JAK1 and IL10R2 with Tyk2 [[4],[185]]. After activation by JAK, STAT dimer molecules like STAT1 and STAT5 in cytoplasm undergo a conformational switch, relocate to the nucleus and bind to DNA as transcription factors to IL10-responsive genes [[186],[187]]. The number of genes regulated by IL-10 is numbering up to thousands with new genes discovered each year [[4],[188]].

The biological effects of IL-10 on innate immune cells suppress the release of immune mediators, antigen expression and phagocytosis [[178]]. Indeed, in vitro inflammation models show that IL-10 prevents PMNL activation and TNF-α as well as IL-8 release after LPS administration [[189]]. Studies with human umbilical vein epithelial cells (HUVEC) display that IL-10 attenuates TNF-α induced ROS production, ICAM-1 expression, and leukocyte adhesion to HUVEC [[190]]. Recent research of monocyte models in vitro designate upregulation of ubiquitin ligases by IL-10 as the mechanism to sequestrate major histocompatibility complex (MHC) complexes and thus inhibit antigen presentation by antigen presenting cells (APCs) [[191]]. The overall influence on chemotaxis of monocytes is, however, rather low [[192]]. What is more, IL-10 knockout mice suffer from cardiac and vascular dysfunction due to an upsurge of COX-2 activity and production of prostaglandins indicating an important role in the suppression of COX by IL-10 [[193]]. Additionally, phagocytic cells are protected against complement lysis infused by an anti-MHC antibody or binding of zymosan when administered IL-10 compared to control cells in vitro [[194]]. Nevertheless, IL-10 plays an important role in suppressing inflammation in mucosa cells evident by IL-10 knockout mice that will develop severe colitis [[195]]. To limit its own properties, IL-10R activation also triggers the transcription of suppressor of cytokine signaling (SOCS)3, thus limiting its own release [[196]]. Albeit, systemic levels of IL-10 were significantly increased in patients with severe sepsis and linked to mortality as compared to patients with moderate sepsis [[197]]. A smaller study comparing 16 septic shock patients with 11 shock patients without sepsis supports the predictive value of systemic IL-10 levels in the first days after admission [[198]]. In case of trauma, a Swiss study reported elevated systemic IL-10 levels in patients with injury (n = 417) and a correlation of IL-10 levels to the severity of the injury as compared to healthy volunteers [[199]]. The development of sepsis in trauma patients was also linked to elevated systemic IL-10 levels on admission in an American study (n = 66) [[200]]. With regard to bone biology, loss of IL-10 exacerbated early Type-1 diabetes-induced bone loss [[201]]. Serum IL-10 levels in systemic lupus erythematosus patients with osteonecrosis were higher than that in those without osteonecrosis [[202]].

6. Interleukin-8

Interleukin-8 was first observed for its trait as a chemoattractant for granulocytes, primarily neutrophils in vitro [[203]]. It is sometimes called chemokine (C-X-C motif) ligand 8 or CXCL-8 and encoded by the CXCL-8 gene [[204]]. Through transfected cell culture models, NF-κB and JNK, as well as AP-1, have been identified as vital pathways for inducible IL-8 expression [[205]]. Every cell with TLR can produce and secrete IL-8 including macrophages and smooth muscle cells [[206]], while endothelial cells accumulate IL-8 in vesicles known as Weibel–Palade bodies [[207]]. Indeed, IL-8 is translated as a 99 amino acid long precursor peptide and cleaved into two active isoforms; one being 77 amino acids long and secreted by endothelial cells in cell culture [[208]]. While the other has a 72 amino acid sequence and is produced by monocytes and other leukocytes [[209]].

The main targets for IL-8 are G-protein coupled receptors CXCR1 and CXCR2, though the latter has a weaker affinity for IL-8 [[210]]. Furthermore, IL-8 guides neutrophils to the direction of inflammation (chemotaxis), which is evident in increased concentrations of this cytokine in lungs of patients with ARDS [[211]]. However, high IL-8 levels are not correlated with the probability of development of ARDS [[212]]. Additionally, IL-8 does not activate NAPDH oxidase directly with in vitro, yet, it enhances the respiratory burst activity by the recruitment of NAPDH oxidase components, N-formyl-methionyl-leucyl-phenylalanine (fMLP) receptor, and P-selectin ligands into lipid drafts [[213]]. In vitro studies with colon cancer cells transfected with IL-8 cDNA displayed a significant rise in cell proliferation, migration, and invasion by these cells [[214]]. This is supported by earlier in vitro investigations with HUVEC where recombinant IL-8 induced endothelial cell proliferation and capillary tube organization [[215]]. In conclusion, IL-8 is a very potent trigger to cell migration and proliferation, and thus should always be considered in inflammation models. A study analyzing systemic IL-8 levels for 60 days after a burn injury in children (n = 468) provided interesting insights [[216]]. The IL-8 levels correlated with the percent of burned total body surface area and were predictive for multiple organ failure and mortality [[216]].

It has to be considered that systemic IL-8 levels do not only provide prognostic value by reading the absolute levels, but rather implicate the duration of sustained high IL-8 levels for diagnosis. For instance, in a study with 27 patients, those with severe sepsis (n = 17) presented high IL-8 plasma levels steadily for 24 h after admission, whereas those with uncomplicated sepsis (n = 10) did not [[217]]. Furthermore, a smaller study with 24 subjects with traumatic brain injury (TBI) linked elevated systemic IL-8 levels upon admission to the worsened outcome [[218]]. This was first reported in a similar Croatian study with 20 TBI patients, with elevated IL-8 plasma levels in the non-survivor group [[219]].

Postmenopausal osteoporosis is characterized by rapid bone loss and IL-8 has been implicated among other pro-inflammatory cytokines to play a role in bone remodeling. There was a significant IL-8 increase in post-menopausal women with osteoporosis and bone loss [[220]]. Atorvastatin, which is known for its pleiotropic effects on bone tissue, decreased IL-8 levels and bone loss of rats subjected to glucocorticoid-induced osteoporosis [[221]]. RANKL-expressing neutrophils are increased in male patients with Chronic obstructive pulmonary disease (COPD), and furthermore, associated with bone mineral density and lung function, suggesting that these cells play a role in osteoclastogenesis in COPD [[222]]. Plasma levels of IL-8 were increased in COPD patients and correlated with RANKL expression by neutrophils [[223]].

7. Limitations

This review only provides a short overview of selected cytokines that are important for inflammatory reactions of the body. However, one should note that hundreds of other cytokines, hormones, and proteins mediate the immune dysregulation as seen in many patients with inflammatory states like sepsis or after trauma. A more comprehensive overview about immune dysregulation in shock/sepsis is given by Angus and van der Poll, as well as Rittirsch et al. [[224],[225]]. Also, large randomized controlled trials or meta-analysis for clinical value of the mentioned cytokines are still missing. The overall data is still too weak to give a definite clinical evaluation.

References

  1. Osamu Takeuchi; Shizuo Akira; Pattern Recognition Receptors and Inflammation. Cell 2010, 140, 805-820, 10.1016/j.cell.2010.01.022.
  2. Fred Schaper; Stefan Rose-John; Interleukin-6: Biology, signaling and strategies of blockade. Cytokine & Growth Factor Reviews 2015, 26, 475-487, 10.1016/j.cytogfr.2015.07.004.
  3. Jennifer R. Tisoncik; Marcus J. Korth; Cameron P. Simmons; Jeremy Farrar; Thomas R. Martin; Michael G. Katze; Into the Eye of the Cytokine Storm. Microbiology and Molecular Biology Reviews 2012, 76, 16-32, 10.1128/MMBR.05015-11.
  4. Jens Geginat; Paola Larghi; Moira Paroni; Giulia Nizzoli; Alessandra Penatti; Massimiliano Pagani; Nicola Gagliani; Pier Luigi Meroni; Sergio Abrignani; Richard A. Flavell; et al. The light and the dark sides of Interleukin-10 in immune-mediated diseases and cancer.. Cytokine & Growth Factor Reviews 2016, 30, 87-93, 10.1016/j.cytogfr.2016.02.003.
  5. Israel F. Charo; Richard M. Ransohoff; The Many Roles of Chemokines and Chemokine Receptors in Inflammation. New England Journal of Medicine 2006, 354, 610-621, 10.1056/nejmra052723.
  6. Charles A. Dinarello; Immunological and Inflammatory Functions of the Interleukin-1 Family. Annual Review of Immunology 2009, 27, 519-550, 10.1146/annurev.immunol.021908.132612.
  7. José Noel Ibrahim; Isabelle Jéru; Jean-Claude Lecron; Myrna Medlej-Hashim; Cytokine signatures in hereditary fever syndromes (HFS). Cytokine & Growth Factor Reviews 2017, 33, 19-34, 10.1016/j.cytogfr.2016.11.001.
  8. Stefan Rose-John; Interleukin-6 Family Cytokines. Cold Spring Harbor Perspectives in Biology 2017, 10, a028415, 10.1101/cshperspect.a028415.
  9. Sean Diehl; Mercedes Rincón; The two faces of IL-6 on Th1/Th2 differentiation. Molecular Immunology 2002, 39, 531-536, 10.1016/s0161-5890(02)00210-9.
  10. Toshio Hirano; Kiyoshi Yasukawa; Hisashi Harada; Tetsuya Taga; Yasuo Watanabe; Tadashi Matsuda; Shin-Ichiro Kashiwamura; Koichi Nakajima; Koichi Koyama; Akihiro Iwamatsu; et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986, 324, 73-76, 10.1038/324073a0.
  11. Masahiko Hibi; Masaaki Murakami; Mikiyoshi Saito; Toshio Hirano; Tetsuya Taga; Tadamitsu Kishimoto; Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 1990, 63, 1149-1157, 10.1016/0092-8674(90)90411-7.
  12. Peter C. Heinrich; Iris Behrmann; Serge Haan; Heike M. Hermanns; Gerhard Müller-Newen; Fred Schaper; Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical Journal 2003, 374, 1-20, 10.1042/bj20030407.
  13. Simone Radtke; Stefan Wüller; Xiang-Ping Yang; Barbara E. Lippok; Barbara Mütze; Christine Mais; Hildegard Schmitz-Van De Leur; Johannes G. Bode; Matthias Gaestel; Peter C. Heinrich; et al. Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation. Journal of Cell Science 2010, 123, 947-959, 10.1242/jcs.065326.
  14. Martin J. Boulanger; Dar-Chone Chow; Elena E. Brevnova; K. Christopher Garcia; Hexameric Structure and Assembly of the Interleukin-6/IL-6 -Receptor/gp130 Complex. Science 2003, 300, 2101-2104, 10.1126/science.1083901.
  15. Nathalie Franchimont; Pascale Huynen; Clio Ribbens; Biserka Relic; Alain Chariot; Vincent Bours; Jacques Piette; Marie-Paule Merville; Michel Malaise; Interleukin-6 receptor shedding is enhanced by interleukin-1? and tumor necrosis factor ? and is partially mediated by tumor necrosis factor ?-converting enzyme in osteoblast-like cells. Arthritis Care & Research 2005, 52, 84-93, 10.1002/art.20727.
  16. I. Walev; P. Vollmer; M. Palmer; S. Bhakdi; S. Rose-John; Pore-forming toxins trigger shedding of receptors for interleukin 6 and lipopolysaccharide.. Proceedings of the National Academy of Sciences 1996, 93, 7882-7887, 10.1073/pnas.93.15.7882.
  17. John A. Lust; Kathleen A. Donovan; Michael P. Kline; Philip R. Greipp; Robert A. Kyle; Nita J. Maihle; Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 1992, 4, 96-100, 10.1016/1043-4666(92)90043-q.
  18. Christopher A Hunter; Simon A Jones; IL-6 as a keystone cytokine in health and disease. Nature Immunology 2015, 16, 448-457, 10.1038/ni.3153.
  19. Jorge M. Luna; Yeseon P. Moon; Khin M. Liu; Steven Spitalnik; Myunghee C. Paik; Keun Cheung; Ralph L. Sacco; Mitchell S. V. Elkind; High-sensitivity C-reactive protein and interleukin-6-dominant inflammation and ischemic stroke risk: the northern Manhattan study.. Stroke 2014, 45, 979-987, 10.1161/STROKEAHA.113.002289.
  20. Barbara Mroczko; Magdalena Groblewska; Mariusz Gryko; Bogusław Kędra; Maciej Szmitkowski; Diagnostic usefulness of serum interleukin 6 (IL-6) and C-reactive protein (CRP) in the differentiation between pancreatic cancer and chronic pancreatitis. Journal of Clinical Laboratory Analysis 2010, 24, 256-261, 10.1002/jcla.20395.
  21. Vincenzo Panichi; Umberto Maggiore; Daniele Taccola; Massimiliano Migliori; Giovanni Manca Rizza; Cristina Consani; Alessio Bertini; Stefano Sposini; Rafael Perez-Garcia; Paolo Rindi; et al. Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrology Dialysis Transplantation 2004, 19, 1154-1160, 10.1093/ndt/gfh052.
  22. Suzanne M Hurst; Thomas S Wilkinson; Rachel M McLoughlin; Suzanne Jones; Sankichi Horiuchi; Naoki Yamamoto; Stefan Rose-John; Gerald M Fuller; Nicholas Topley; Simon A Jones; et al. IL-6 and Its Soluble Receptor Orchestrate a Temporal Switch in the Pattern of Leukocyte Recruitment Seen during Acute Inflammation. Immunity 2001, 14, 705-714, 10.1016/s1074-7613(01)00151-0.
  23. Qing Chen; Daniel T Fisher; Kristen A Clancy; Jean-Marc M Gauguet; Wan-Chao Wang; Emily Unger; Stefan Rose-John; Ulrich H Von Andrian; Heinz Baumann; Sharon S Evans; et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nature Immunology 2006, 7, 1299-1308, 10.1038/ni1406.
  24. Brendan J. Jenkins; Dianne Grail; Melissa Inglese; Cathy Quilici; Steven Bozinovski; Peter Wong; Matthias Ernst; Imbalanced gp130-Dependent Signaling in Macrophages Alters Macrophage Colony-Stimulating Factor Responsiveness via Regulation of c-fms Expression. Molecular and Cellular Biology 2004, 24, 1453-1463, 10.1128/MCB.24.4.1453-1463.2004.
  25. Rachel M. McLoughlin; Brendan J. Jenkins; Dianne Grail; Anwen S. Williams; Ceri A. Fielding; Clare R. Parker; Matthias Ernst; Nicholas Topley; Simon A. Jones; IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proceedings of the National Academy of Sciences 2005, 102, 9589-9594, 10.1073/pnas.0501794102.
  26. Sergei Grivennikov; Eliad Karin; Janos Terzic; Daniel Mucida; Guann-Yi Yu; Sivakumar Vallabhapurapu; Jürgen Scheller; Stefan Rose-John; Hilde Cheroutre; Lars Eckmann; et al. IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer. Cancer Cell 2009, 15, 103-113, 10.1016/j.ccr.2009.02.003.
  27. Michael Luig; Malte A. Kluger; Boeren Goerke; Matthias Meyer; Anna Nosko; Isabell Yan; Jürgen Scheller; Hans-Willi Mittrücker; Stefan Rose-John; Rolf A.K. Stahl; et al. Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN. Journal of the American Society of Nephrology 2015, 26, 1597-1607, 10.1681/ASN.2014060620.
  28. Hong Zhang; Patrick Neuhöfer; Liang Song; Björn Rabe; Marina Lesina; Magdalena U. Kurkowski; Matthias Treiber; Thomas Wartmann; Sara Regnér; Henrik Thorlacius; et al. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality.. Journal of Clinical Investigation 2013, 123, 1019-1031, 10.1172/JCI64931.
  29. Michel Jourdan; Régis Bataille; Jacques Seguin; Xue Guang Zhang; Paul André Chaptal; Bernard Klein; Constitutive production of interleukin-6 and immunologic features in cardiac myxomas. Arthritis Care & Research 1990, 33, 398-402, 10.1002/art.1780330313.
  30. Sonia A. Duffy; Jeremy M.G. Taylor; Jeffrey E. Terrell; Mozaffarul Islam; Yun Li; Karen E. Fowler; Gregory T. Wolf; Theodoros N. Teknos; Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 2008, 113, 750-757, 10.1002/cncr.23615.
  31. Guitao Zhang; Chi Man Tsang; Wen Deng; Yim Ling Yip; Vivian Wai-Yan Lui; Sze Chuen Cesar Wong; Annie Lai-Man Cheung; Pok Man Hau; Musheng Zeng; Maria Li Lung; et al. Enhanced IL-6/IL-6R Signaling Promotes Growth and Malignant Properties in EBV-Infected Premalignant and Cancerous Nasopharyngeal Epithelial Cells. PLOS ONE 2013, 8, e62284, 10.1371/journal.pone.0062284.
  32. Yan, L.; Hu, R.; Tu, S.; Cheng, W.J.; Zheng, Q.; Wang, J.W.; Kan, W.S.; Ren, Y.J. Meta-analysis of association between IL-6 -634C/G polymorphism and osteoporosis. Genet. Mol. Res. 2015, 14, 19225–19232.
  33. Zhao Wang; Yonghong Yang; Minjuan He; Ran Wang; Juming Ma; Yimin Zhang; Lingyun Zhao; Ke Yu; Association Between Interleukin-6 Gene Polymorphisms and Bone Mineral Density: A Meta-Analysis. Genetic Testing and Molecular Biomarkers 2013, 17, 898-909, 10.1089/gtmb.2013.0223.
  34. Yuanyuan Ni; Hua Li; Yang Zhang; Hao Zhang; Yongchu Pan; Junqing Ma; Lin Wang; Association of IL-6 G-174C polymorphism with bone mineral density. Journal of Bone and Mineral Metabolism 2013, 32, 167-173, 10.1007/s00774-013-0477-2.
  35. Konrad Reinhart; Michael Meißner; Frank Martin Brunkhorst; Markers for Sepsis Diagnosis: What is Useful?. Critical Care Clinics 2006, 22, 503-519, 10.1016/j.ccc.2006.03.003.
  36. A. M. Cruickshank; W. D. Fraser; H. J. G. Burns; J. Van Damme; A. Shenkin; Response of Serum Interleukin-6 in Patients Undergoing Elective Surgery of Varying Severity. Clinical Science 1990, 79, 161-165, 10.1042/cs0790161.
  37. Lori F. Gentile; Alex G. Cuenca; Erin L. VanZant; Philip A. Efron; Bruce McKinley; Frederick Moore; Lyle L. Moldawer; Is there value in plasma cytokine measurements in patients with severe trauma and sepsis?. Methods 2013, 61, 3-9, 10.1016/j.ymeth.2013.04.024.
  38. L. Kitanovski; J. Jazbec; S. Hojker; M. Gubina; M. Derganc; Diagnostic accuracy of procalcitonin and interleukin-6 values for predicting bacteremia and clinical sepsis in febrile neutropenic children with cancer. European Journal of Clinical Microbiology & Infectious Diseases 2006, 25, 413-415, 10.1007/s10096-006-0143-x.
  39. C. Haasper; M. Kalmbach; G.D. Dikos; R. Meller; Christian W. Müller; C. Krettek; F. Hildebrand; M. Frink; Prognostic value of procalcitonin (PCT) and/or interleukin-6 (IL-6) plasma levels after multiple trauma for the development of multi organ dysfunction syndrome (MODS) or sepsis. Technology and Health Care 2010, 18, 89-100, 10.3233/thc-2010-0571.
  40. Luis Alberto Pallás Beneyto; Olga Rodríguez Luis; Carmen Saiz Sánchez; Oscar Cotell Simón; Daniel Bautista Rentero; Vicente Miguel Bayarri; Valor pronóstico de la interleucina 6 en la mortalidad de pacientes con sepsis. Medicina Clínica 2016, 147, 281-286, 10.1016/j.medcli.2016.06.001.
  41. C. A. Dinarello; Demonstration and characterization of two distinct human leukocytic pyrogens. The Journal of Experimental Medicine 1974, 139, 1369-1381, 10.1084/jem.139.6.1369.
  42. Charles A. Dinarello; Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011, 117, 3720-3732, 10.1182/blood-2010-07-273417.
  43. Nelson C Di Paolo; Dmitry M Shayakhmetov; Interleukin 1α and the inflammatory process.. Nature Immunology 2016, 17, 906-913, 10.1038/ni.3503.
  44. Mihai G. Netea; Frank L. Van De Veerdonk; Jos W.M. Van Der Meer; Charles A. Dinarello; Leo A.B. Joosten; Inflammasome-Independent Regulation of IL-1-Family Cytokines. Annual Review of Immunology 2015, 33, 49-77, 10.1146/annurev-immunol-032414-112306.
  45. Marina Bersudsky; Lotem Luski; Daniel Fishman; Rosalyn M White; Nadya Ziv-Sokolovskaya; Shahar Dotan; Peleg Rider; Irena Kaplanov; Tegest Aychek; Charles A Dinarello; et al. Non-redundant properties of IL-1α and IL-1β during acute colon inflammation in mice. Gut 2013, 63, 598-609, 10.1136/gutjnl-2012-303329.
  46. Donald A. McCarthy; Aparna Ranganathan; Sita Subbaram; Nicole L. Flaherty; Nilay Patel; Mohamed Trebak; Nadine Hempel; J. Andres Melendez; Redox-control of the alarmin, Interleukin-1α.. Redox Biology 2013, 1, 218-225, 10.1016/j.redox.2013.03.001.
  47. Busun Kim; Youngmin Lee; Eunsom Kim; Areum Kwak; Soyoon Ryoo; Seung Hyeon Bae; Tania Azam; Soohyun Kim; Charles A. Dinarello; The Interleukin-1α Precursor is Biologically Active and is Likely a Key Alarmin in the IL-1 Family of Cytokines. Frontiers in Immunology 2013, 4, no, 10.3389/fimmu.2013.00391.
  48. H. Kimura; Y. Inukai; T. Takii; Y. Furutani; Y. Shibata; H. Hayashi; S. Sakurada; T. Okamoto; J.-I. Inoue; Y. Oomoto; et al. Molecular analysis of constitutive IL-1alpha gene expression in human melanoma cells: Autocrine stimulation through NF-kappaB activation by endogenous IL-1alpha. Cytokine 1998, 10, 872-879, 10.1006/cyto.1998.0369.
  49. Olaf Groß; Amir S. Yazdi; Christina J. Thomas; Mark Masin; Leonhard X. Heinz; Greta Guarda; Manfredo Quadroni; Stefan K. Drexler; Jurg Tschopp; Inflammasome Activators Induce Interleukin-1α Secretion via Distinct Pathways with Differential Requirement for the Protease Function of Caspase-1. Immunity 2012, 36, 388-400, 10.1016/j.immuni.2012.01.018.
  50. K Kuida; J. Lippke; G Ku; M. Harding; D. Livingston; M. Su; R. Flavell; Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 1995, 267, 2000-2003, 10.1126/science.7535475.
  51. F Re; R Bertini; M Sironi; J. Giri; S. Dower; J. Sims; F Colotta; M Muzio; N Polentarutti; A Mantovani; et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 1993, 261, 472-475, 10.1126/science.8332913.
  52. Florence Anquetil; Somayeh Sabouri; Charles Thivolet; Teresa Rodriguez-Calvo; Jose Zapardiel-Gonzalo; Natalie Amirian; Darius Schneider; Ericka Castillo; Yasaman Lajevardi; Matthias G. Von Herrath; et al. Alpha cells, the main source of IL-1β in human pancreas.. Journal of Autoimmunity 2017, 81, 68-73, 10.1016/j.jaut.2017.03.006.
  53. Peter Libby; Interleukin-1 Beta as a Target for Atherosclerosis Therapy: Biological Basis of CANTOS and Beyond.. Journal of the American College of Cardiology 2017, 70, 2278-2289, 10.1016/j.jacc.2017.09.028.
  54. Laetitia Agostini; Fabio Martinon; Kimberly Burns; Michael F. McDermott; Philip N. Hawkins; Jurg Tschopp; NALP3 Forms an IL-1β-Processing Inflammasome with Increased Activity in Muckle-Wells Autoinflammatory Disorder. Immunity 2004, 20, 319-325, 10.1016/s1074-7613(04)00046-9.
  55. Franz G Bauernfeind; Gabor Horvath; Andrea Stutz; Emad S. Alnemri; Kelly Macdonald; David Speert; Teresa Fernandes-Alnemri; Jianghong Wu; Brian G. Monks; Katherine A. Fitzgerald; et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.. The Journal of Immunology 2009, 183, 787-791, 10.4049/jimmunol.0901363.
  56. Yan Qu; Luigi Franchi; Gabriel Nunez; George R. Dubyak; Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages. The Journal of Immunology 2007, 179, 1913-1925, 10.4049/jimmunol.179.3.1913.
  57. Marco Gattorno; Sara Tassi; Sonia Carta; Laura Delfino; Francesca Ferlito; Maria Antonietta Pelagatti; Andrea D'osualdo; Antonella Buoncompagni; Maria Giannina Alpigiani; Maria Alessio; et al. Pattern of interleukin-1β secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients withCIAS1 mutations. Arthritis Care & Research 2007, 56, 3138-3148, 10.1002/art.22842.
  58. Fabio Martinon; Kimberly Burns; Jürg Tschopp; The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta.. F1000 - Post-publication peer review of the biomedical literature 2002, 10, 417–426, 10.3410/f.1008963.115857.
  59. Junhui Zhen; Le Zhang; Jiachao Pan; Shumin Ma; Xiaojian Yu; Xiaobo Li; Shijun Chen; Wenjun Du; AIM2 Mediates Inflammation-Associated Renal Damage in Hepatitis B Virus-Associated Glomerulonephritis by Regulating Caspase-1, IL-1β, and IL-18. Mediators of Inflammation 2014, 2014, 190860, 10.1155/2014/190860.
  60. Hal M. Hoffman; James L. Mueller; David H. Broide; Alan A. Wanderer; Richard D. Kolodner; Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome.. Nature Genetics 2001, 29, 301-305, 10.1038/ng756.
  61. Jérôme Feldmann; Anne-Marie Prieur; Pierre Quartier; Patrick Berquin; Stephanie Certain; Elisabetta Cortis; Dominique Teillac-Hamel; Alain Fischer; Genevieve De Saint Basile; Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and Chondrocytes. The American Journal of Human Genetics 2002, 71, 198-203, 10.1086/341357.
  62. Ivona Aksentijevich; Miroslawa Nowak; Mustapha Mallah; Jae Jin Chae; Wendy T. Watford; Sigrun R. Hofmann; Leonard Stein; Ricardo Russo; Donald Goldsmith; Peter Dent; et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.. Arthritis Care & Research 2002, 46, 3340-3348, 10.1002/art.10688.
  63. L. Cuisset; I. Jéru; B. Dumont; A Fabre; E. Cochet; J. Le Bozec; M. Delpech; S. Amselem; I. Touitou; and the French CAPS study group; et al. Mutations in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Annals of the Rheumatic Diseases 2010, 70, 495-499, 10.1136/ard.2010.138420.
  64. Nienke M Ter Haar; Marlen Oswald; Jerold Jeyaratnam; Jordi Anton; Karyl S Barron; Paul A Brogan; Luca Cantarini; Caroline Galeotti; Gilles Grateau; Véronique Hentgen; et al. Recommendations for the management of autoinflammatory diseases. Annals of the Rheumatic Diseases 2015, 74, 1636-1644, 10.1136/annrheumdis-2015-207546.
  65. Emmanuelle C. Landmann; Ulrich A. Walker; Pharmacological treatment options for cryopyrin-associated periodic syndromes. Expert Review of Clinical Pharmacology 2017, 10, 855-864, 10.1080/17512433.2017.1338946.
  66. Peter Duewell; Hajime Kono; Katey J. Rayner; Cherilyn M. Sirois; Gregory Vladimer; Franz G. Bauernfeind; George S. Abela; Luigi Franchi; Gabriel Núñez; Max Schnurr; et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.. Nature 2010, 464, 1357-1361, 10.1038/nature08938.
  67. Hirokazu Kirii; Tamikazu Niwa; Yasuhiro Yamada; Hisayasu Wada; Kuniaki Saito; Yoichiro Iwakura; Masahide Asano; Hisataka Moriwaki; Mitsuru Seishima; Lack of Interleukin-1β Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice. Arteriosclerosis, Thrombosis, and Vascular Biology 2003, 23, 656-660, 10.1161/01.atv.0000064374.15232.c3.
  68. Tim Hendrikx; Mike L. J. Jeurissen; Patrick J. Van Gorp; Marion J. Gijbels; Sofie M. A. Walenbergh; Tom Houben; Rick Van Gorp; Chantal C. Pöttgens; Rinke Stienstra; Mihai G. Netea; et al. Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development inLdlr−/−mice. The FEBS Journal 2015, 282, 2327-2338, 10.1111/febs.13279.
  69. Fei Zheng; Shanshan Xing; Zushun Gong; Wei Mu; Qichong Xing; Silence of NLRP3 Suppresses Atherosclerosis and Stabilizes Plaques in Apolipoprotein E-Deficient Mice. Mediators of Inflammation 2014, 2014, 507208, 10.1155/2014/507208.
  70. P Menu; M Pellegrin; J-F Aubert; K Bouzourene; A Tardivel; L Mazzolai; J Tschopp; Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome.. Cell Death & Disease 2011, 2, e137-e137, 10.1038/cddis.2011.18.
  71. Yugang Jiang; Mian Wang; Kai Huang; Zhihui Zhang; Nan Shao; Yuanqi Zhang; Wenjian Wang; Shenming Wang; Oxidized low-density lipoprotein induces secretion of interleukin-1β by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochemical and Biophysical Research Communications 2012, 425, 121-126, 10.1016/j.bbrc.2012.07.011.
  72. Sin Jee Son; Ki-Jong Rhee; Jaewon Lim; Tae Ue Kim; Tack-Joong Kim; Yoon Suk Kim; Triglyceride-induced macrophage cell death is triggered by caspase-1.. Biological and Pharmaceutical Bulletin 2013, 36, 108-113, 10.1248/bpb.b12-00571.
  73. C. Guo; R. Fu; S. Wang; Y. Huang; X. Li; M. Zhou; J. Zhao; N. Yang; NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clinical & Experimental Immunology 2018, 194, 231-243, 10.1111/cei.13167.
  74. Sirish K. Ippagunta; David D. Brand; Jiwen Luo; Kelli L. Boyd; Christopher Calabrese; Rinke Stienstra; Frank L. Van De Veerdonk; Mihai G. Netea; Leo A. B. Joosten; Mohamed Lamkanfi; et al. Inflammasome-independent Role of Apoptosis-associated Speck-like Protein Containing a CARD (ASC) in T Cell Priming Is Critical for Collagen-induced Arthritis*. Journal of Biological Chemistry 2010, 285, 12454-12462, 10.1074/jbc.M109.093252.
  75. Leo A. B. Joosten; Mihai G. Netea; Giamila Fantuzzi; Marije I. Koenders; Monique M. A. Helsen; Helmut Sparrer; Christine T. Pham; Jos W. M. Van Der Meer; Charles A. Dinarello; Wim B. Van Den Berg; et al. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1beta.. Arthritis Care & Research 2009, 60, 3651-3662, 10.1002/art.25006.
  76. Lieselotte Vande Walle; Nina Van Opdenbosch; Peggy Jacques; Amelie Fossoul; Eveline Verheugen; Peter Vogel; Rudi Beyaert; Dirk Elewaut; Thirumala-Devi Kanneganti; Geert Van Loo; et al. Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature 2014, 512, 69-73, 10.1038/nature13322.
  77. Christianna Choulaki; Garyfallia Papadaki; Argyro Repa; Eleni Kampouraki; Konstantinos Kambas; Konstantinos Ritis; George Bertsias; Dimitrios T. Boumpas; Prodromos Sidiropoulos; Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis.. Arthritis Research & Therapy 2015, 17, 257, 10.1186/s13075-015-0775-2.
  78. Piero Ruscitti; Paola Cipriani; Paola Di Benedetto; Vasiliki Liakouli; O. Berardicurti; Francesco Carubbi; Francesco Ciccia; Saverio Alvaro; Giovanni Triolo; Roberto Giacomelli; et al. Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1β via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a pos. Clinical & Experimental Immunology 2015, 182, 35-44, 10.1111/cei.12667.
  79. Tae-Hoon Shin; Hyung-Sik Kim; Tae-Wook Kang; Byung-Chul Lee; Hwa-Yong Lee; Yoon-Jin Kim; Ji-Hee Shin; Yoojin Seo; Soon Won Choi; Seunghee Lee; et al. Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis.. Cell Death & Disease 2016, 7, e2524-e2524, 10.1038/cddis.2016.442.
  80. Jiangdong Sui; Hua Li; Yongfei Fang; Yang Liu; Minhui Li; Bing Zhong; Fei Yang; Qiang Zou; Yuzhang Wu; NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in Han Chinese. Arthritis Care & Research 2012, 64, 647-654, 10.1002/art.33370.
  81. Lei Zhang; Yubo Dong; Fangpeng Zou; Min Wu; Changchun Fan; Yaohai Ding; 11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. International Immunopharmacology 2013, 17, 489-494, 10.1016/j.intimp.2013.07.015.
  82. Faxin Li; Nongjian Guo; Yuxia Ma; Bin Ning; Yan Wang; Liqing Kou; Inhibition of P2X4 Suppresses Joint Inflammation and Damage in Collagen-Induced Arthritis. Inflammation 2013, 37, 146-153, 10.1007/s10753-013-9723-y.
  83. Sylvie Grandemange; Elodie Sanchez; Pascale Louis-Plence; Frédéric Tran Mau-Them; Didier Bessis; Christine Coubes; Eric Frouin; Marieke Seyger; Manon Girard; Jacques Puechberty; et al. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-associated autoinflammation with arthritis and dyskeratosis). Annals of the Rheumatic Diseases 2016, 76, 1191-1198, 10.1136/annrheumdis-2016-210021.
  84. Mohd Nizam Mansoori; Priyanka Shukla; Manisha Kakaji; Abdul M Tyagi; Kamini Srivastava; Manoj Shukla; Manisha Dixit; Jyoti Kureel; Sushil Gupta; Divya Singh; et al. IL-18BP is decreased in osteoporotic women: Prevents Inflammasome mediated IL-18 activation and reduces Th17 differentiation. Scientific Reports 2016, 6, 33680, 10.1038/srep33680.
  85. Lijun Xu; Lixia Zhang; Zhifang Wang; Chong Li; Shan Li; Li Li; Qianying Fan; Lili Zheng; Melatonin Suppresses Estrogen Deficiency-Induced Osteoporosis and Promotes Osteoblastogenesis by Inactivating the NLRP3 Inflammasome. Calcified Tissue International 2018, 103, 400-410, 10.1007/s00223-018-0428-y.
  86. John N. Snouwaert; MyTrang Nguyen; Peter W. Repenning; Rebecca Dye; Eric W. Livingston; Martina Kovarova; Sheryl S. Moy; Brian E. Brigman; Ted A. Bateman; Jenny P.-Y. Ting; et al. An NLRP3 Mutation Causes Arthropathy and Osteoporosis in Humanized Mice.. Cell Reports 2016, 17, 3077-3088, 10.1016/j.celrep.2016.11.052.
  87. Hyun Young Kim; Kyeong Seok Kim; Myung Ji Kim; Hyung-Shik Kim; Kwang-Youl Lee; Keon Wook Kang; Auranofin Inhibits RANKL-Induced Osteoclastogenesis by Suppressing Inhibitors of κB Kinase and Inflammasome-Mediated Interleukin-1β Secretion.. Oxidative Medicine and Cellular Longevity 2019, 2019, 3503912, 10.1155/2019/3503912.
  88. Linghao Wang; Ke Chen; Xinxing Wan; Fang Wang; Zi Guo; Zhaohui Mo; NLRP3 inflammasome activation in mesenchymal stem cells inhibits osteogenic differentiation and enhances adipogenic differentiation. Biochemical and Biophysical Research Communications 2017, 484, 871-877, 10.1016/j.bbrc.2017.02.007.
  89. Wei Chi; Hongrui Chen; Fei Li; Yingting Zhu; Wei Yin; Yehong Zhuo; HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma. Journal of Neuroinflammation 2015, 12, 137, 10.1186/s12974-015-0360-2.
  90. Wei Chi; Fei Li; Hongrui Chen; Yandong Wang; Yingting Zhu; Xuejiao Yang; Jie Zhu; Frances Wu; Hong Ouyang; Jian Ge; et al. Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma. Proceedings of the National Academy of Sciences 2014, 111, 11181-11186, 10.1073/pnas.1402819111.
  91. Matthew Campbell; Sarah L. Doyle; An eye on the future of inflammasomes and drug development in AMD. Journal of Molecular Medicine 2013, 91, 1059-1070, 10.1007/s00109-013-1050-0.
  92. Sarah L Doyle; Matthew Campbell; Ema Ozaki; Robert G Salomon; Andrés Mori; Paul F Kenna; Gwyneth Jane Farrar; Anna-Sophia Kiang; Marian M Humphries; Ed C Lavelle; et al. NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components.. Nature Medicine 2012, 18, 791-798, 10.1038/nm.2717.
  93. Cristhian J. Ildefonso; Manas R. Biswal; Chulbul M. Ahmed; Alfred S. Lewin; The NLRP3 Inflammasome and its Role in Age-Related Macular Degeneration. Advances in Experimental Medicine and Biology 2015, 854, 59-65, 10.1007/978-3-319-17121-0_9.
  94. P Yerramothu; A K Vijay; M D P Willcox; Inflammasomes, the eye and anti-inflammasome therapy. Eye 2017, 32, 491-505, 10.1038/eye.2017.241.
  95. Borna Relja; J. P. Horstmann; K. Kontradowitz; K. Jurida; A. Schaible; C. Neunaber; E. Oppermann; I. Marzi; Nlrp1 inflammasome is downregulated in trauma patients. Journal of Molecular Medicine 2015, 93, 1391-1400, 10.1007/s00109-015-1320-0.
  96. Juan Pablo De Rivero Vaccari; George Lotocki; Ofelia F. Alonso; Helen M. Bramlett; W. Dalton Dietrich; Robert W. Keane; Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury.. British Journal of Pharmacology 2009, 29, 1251-1261, 10.1038/jcbfm.2009.46.
  97. Martina Kovarova; Pamela R. Hesker; Leigh Jania; MyTrang Nguyen; John N. Snouwaert; Zhidan Xiang; Stephen E. Lommatzsch; Max T. Huang; Jenny P.-Y. Ting; Beverly H. Koller; et al. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice.. The Journal of Immunology 2012, 189, 2006-2016, 10.4049/jimmunol.1201065.
  98. Nadine Kerr; Stephanie W. Lee; Jon Perez-Barcena; Catalina Crespi; Javier Ibañez; M. Ross Bullock; W. Dalton Dietrich; Robert W. Keane; Juan Pablo De Rivero Vaccari; Inflammasome proteins as biomarkers of traumatic brain injury. PLOS ONE 2018, 13, e0210128, 10.1371/journal.pone.0210128.
  99. An-Qiang Zhang; Ling Zeng; Wei Gu; Lian-Yang Zhang; Jian Zhou; Dong-Po Jiang; Ding-Yuan Du; Ping Hu; Ce Yang; Jun Yan; et al. Clinical relevance of single nucleotide polymorphisms within the entire NLRP3 gene in patients with major blunt trauma. Critical Care 2011, 15, R280-R280, 10.1186/cc10564.
  100. Nima Hosseinian; Young Cho; Richard F. Lockey; Narasaiah Kolliputi; The role of the NLRP3 inflammasome in pulmonary diseases. Therapeutic Advances in Respiratory Disease 2015, 9, 188-197, 10.1177/1753465815586335.
  101. Heather D. Jones; Timothy R. Crother; Romer A. Gonzalez-Villalobos; Madhulika Jupelli; Shuang Chen; Jargalsaikhan Dagvadorj; Moshe Arditi; Kenichi Shimada; The NLRP3 Inflammasome Is Required for the Development of Hypoxemia in LPS/Mechanical Ventilation Acute Lung Injury. American Journal of Respiratory Cell and Molecular Biology 2013, 50, 270-280, 10.1165/rcmb.2013-0087OC.
  102. Maria T. Kuipers; Hamid Aslami; John R. Janczy; Koenraad F. Van Der Sluijs; Alexander P. J. Vlaar; Esther K. Wolthuis; Goda Choi; Joris J. T. H. Roelofs; Richard A. Flavell; Fayyaz S. Sutterwala; et al. Ventilator-induced Lung Injury Is Mediated by the NLRP3 Inflammasome. Anesthesiology 2012, 116, 1104-1115, 10.1097/aln.0b013e3182518bc0.
  103. Nadine A. Kerr; Juan Pablo De Rivero Vaccari; Sam Abbassi; Harmanpreet Kaur; Ronald Zambrano; Shu Wu; W. Dalton Dietrich; Robert W. Keane; Traumatic Brain Injury-Induced Acute Lung Injury: Evidence for Activation and Inhibition of a Neural-Respiratory-Inflammasome Axis. Journal of Neurotrauma 2018, 35, 2067-2076, 10.1089/neu.2017.5430.
  104. Peng Zou; Xiaoxiao Liu; Gang Li; Yangang Wang; Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1.. Molecular Medicine Reports 2017, 17, 3212-3217, 10.3892/mmr.2017.8241.
  105. Osuka, A.; Hanschen, M.; Stoecklein, V.; Lederer, J.A.; A Protective Role for Inflammasome Activation Following Injury-Shock 2012;37(1). SHOCK Shock, 37, 47-55, 10.1097/shk.0b013e318260d7eb.
  106. Xin Xu; Dongpei Yin; Honglei Ren; Weiwei Gao; Fei Li; Ngdong Sun; Yingang Wu; Shuai Zhou; Li Lyu; Mengchen Yang; et al. Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury.. Neurobiology of Disease 2018, 117, 15-27, 10.1016/j.nbd.2018.05.016.
  107. Wu Jiang; Maoqiang Li; Fan He; Shaobo Zhou; Liulong Zhu; Targeting the NLRP3 inflammasome to attenuate spinal cord injury in mice. Journal of Neuroinflammation 2017, 14, 207, 10.1186/s12974-017-0980-9.
  108. Junwen Qu; Zhiqing Yuan; Guiyang Wang; Xiaopeng Wang; Kewei Li; The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice. International Immunopharmacology 2019, 70, 147-155, 10.1016/j.intimp.2019.02.016.
  109. Jianru Li; Jingsen Chen; Hangbo Mo; Jingyin Chen; Cong Qian; Feng Yan; Chi Gu; Qiang Hu; Lin Wang; Gao Chen; et al. Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage. Molecular Neurobiology 2015, 53, 2668-2678, 10.1007/s12035-015-9318-8.
  110. Adam Denes; Graham Coutts; Nikolett Lénárt; Sheena M. Cruickshank; Pablo Pelegrín; Joanne Skinner; Nancy Rothwell; Stuart M. Allan; David Brough; AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proceedings of the National Academy of Sciences 2015, 112, 4050-4055, 10.1073/pnas.1419090112.
  111. R. Horai; M. Asano; K. Sudo; H. Kanuka; M. Suzuki; M. Nishihara; M. Takahashi; Yoichiro Iwakura; Production of Mice Deficient in Genes for Interleukin (IL)-1 , IL-1 , IL-1 / , and IL-1 Receptor Antagonist Shows that IL-1 Is Crucial in Turpentine-induced Fever Development and Glucocorticoid Secretion. The Journal of Experimental Medicine 1998, 187, 1463-1475, 10.1084/jem.187.9.1463.
  112. Wendan Cheng; Ngying Wu; Qiang Zuo; Zhen Wang; Weimin Fan; Ginsenoside Rb1 prevents interleukin-1 beta induced inflammation and apoptosis in human articular chondrocytes.. International Orthopaedics 2013, 37, 2065-2070, 10.1007/s00264-013-1990-6.
  113. Charles A. Dinarello; Jos W.M. Van Der Meer; Treating inflammation by blocking interleukin-1 in humans.. Seminars in Immunology 2013, 25, 469-484, 10.1016/j.smim.2013.10.008.
  114. Guangwen Ren; Xin Zhao; Liying Zhang; Jimin Zhang; Andrew L'huillier; Weifang Ling; Arthur I. Roberts; Anh D. Le; Songtao Shi; Changshun Shao; et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression.. The Journal of Immunology 2010, 184, 2321-2328, 10.4049/jimmunol.0902023.
  115. Rana M. Al-Sadi; Thomas Y. Ma; IL-1β Causes an Increase in Intestinal Epithelial Tight Junction Permeability1. The Journal of Immunology 2007, 178, 4641-4649, 10.4049/jimmunol.178.7.4641.
  116. Yaron Carmi; Elena Voronov; Shahar Dotan; Nitza Lahat; Michal Amit Rahat; Mina Fogel; Monika Huszar; Malka R. White; Charles A. Dinarello; Ron N. Apte; et al. The Role of Macrophage-Derived IL-1 in Induction and Maintenance of Angiogenesis. The Journal of Immunology 2009, 183, 4705-4714, 10.4049/jimmunol.0901511.
  117. Elizabeth C Rosser; Kristine Oleinika; Silvia Tonon; Ronan Doyle; Anneleen Bosma; Natalie A Carter; Kathryn A Harris; Simon A Jones; Nigel Klein; Claudia Mauri; et al. Regulatory B cells are induced by gut microbiota–driven interleukin-1β and interleukin-6 production. Nature Medicine 2014, 20, 1334-1339, 10.1038/nm.3680.
  118. Martijn Van Griensven; Zytokine als Marker bei Polytrauma. Der Unfallchirurg 2014, 117, 699-702, 10.1007/s00113-013-2543-6.
  119. A. Nese Citak Kurt; A. Denizmen Aygun; Ahmet Godekmerdan; Abdullah Kurt; Yasar Doğan; Erdal Yilmaz; Serum IL-1β, IL-6, IL-8, and TNF-α Levels in Early Diagnosis and Management of Neonatal Sepsis. Mediators of Inflammation 2007, 2007, 31397, 10.1155/2007/31397.
  120. Mariam Abdulrhman Al-Fadhli; Mohammad Ahmed Saraya; Jafar Abdulrida Qasem; Jiwan S. Sidhu; Evaluation of leptin, interleukin-1 beta and tumor necrosis factor alpha in serum of malaria patients as prognostic markers of treatment outcome. Asian Pacific Journal of Tropical Biomedicine 2014, 4, 441-445, 10.12980/APJTB.4.201414B11.
  121. Raúl De Pablo; Jorge Monserrat; Eduardo Reyes; David Diaz-Martin; Manuel Rodriguez Zapata; Fernando Carballo; Antonio De La Hera; Alfredo Prieto; Melchor Alvarez-Mon; Mortality in Patients With Septic Shock Correlates With Anti-Inflammatory But not Proinflammatory Immunomodulatory Molecules. Journal of Intensive Care Medicine 2011, 26, 125-132, 10.1177/0885066610384465.
  122. N. Maruotti; A. Corrado; F.P. Cantatore; Osteoporosis and rheumatic diseases. Reumatismo 2014, 66, 125-135, 10.4081/reumatismo.2014.785.
  123. Paulo Gustavo Sampaio Lacativa; Maria Lucia Fleiuss De Farias; Osteoporosis and inflammation. Arquivos Brasileiros de Endocrinologia & Metabologia 2010, 54, 123-132, 10.1590/s0004-27302010000200007.
  124. Hai-Feng Gu; Ling-Jia Gu; Yue Wu; Xiao-Hong Zhao; Qing Zhang; Zhe-Rong Xu; Yun-Mei Yang; Efficacy and Safety of Denosumab in Postmenopausal Women With Osteoporosis. Medicine 2015, 94, e1674, 10.1097/MD.0000000000001674.
  125. Nam‐Kyong Choi; Daniel H. Solomon; Theodore N. Tsacogianis; Joan E. Landon; Hong Ji Song; Seoyoung C. Kim; Comparative Safety and Effectiveness of Denosumab Versus Zoledronic Acid in Patients With Osteoporosis: A Cohort Study.. Journal of Bone and Mineral Research 2017, 32, 611-617, 10.1002/jbmr.3019.
  126. Torbjörn Kullenberg; Malin Löfqvist; Mika Leinonen; Raphaela Goldbach-Mansky; Hans Olivecrona; Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes.. Rheumatology 2016, 55, 1499-506, 10.1093/rheumatology/kew208.
  127. Maria Victoria Hernández; Raimon Sanmartí; Juan D. Cañete; The safety of tumor necrosis factor-alpha inhibitors in the treatment of rheumatoid arthritis. Expert Opinion on Drug Safety 2016, 15, 613-624, 10.1517/14740338.2016.1160054.
  128. Ari B. Molofsky; Adam K. Savage; Richard M. Locksley; Interleukin-33 in Tissue Homeostasis, Injury, and Inflammation.. Immunity 2015, 42, 1005-1019, 10.1016/j.immuni.2015.06.006.
  129. Virginie Carriere; Lucie Roussel; Nathalie Ortega; Delphine-Armelle Lacorre; Laure Americh; Luc Aguilar; Gérard Bouche; Jean-Philippe Girard; IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proceedings of the National Academy of Sciences 2006, 104, 282-287, 10.1073/pnas.0606854104.
  130. Mélanie Pichery; Emilie Mirey; Pascale Mercier; Emma Lefrancais; Arnaud Dujardin; Nathalie Ortega; Jean-Philippe Girard; Endogenous IL-33 Is Highly Expressed in Mouse Epithelial Barrier Tissues, Lymphoid Organs, Brain, Embryos, and Inflamed Tissues: In Situ Analysis Using a Novel Il-33–LacZ Gene Trap Reporter Strain. The Journal of Immunology 2012, 188, 3488-3495, 10.4049/jimmunol.1101977.
  131. Gaby Palmer; Brian P. Lipsky; Molly D. Smithgall; David Meininger; Sophia Siu; Dominique Talabot-Ayer; Cem Gabay; Dirk E. Smith; The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine 2008, 42, 358-364, 10.1016/j.cyto.2008.03.008.
  132. Jochen Schmitz; Alexander Owyang; Elizabeth Oldham; Yaoli Song; Erin Murphy; Terril K. McClanahan; Gerard Zurawski; Mehrdad Moshrefi; Jinzhong Qin; Xiaoxia Li; et al. IL-33, an Interleukin-1-like Cytokine that Signals via the IL-1 Receptor-Related Protein ST2 and Induces T Helper Type 2-Associated Cytokines. Immunity 2005, 23, 479-490, 10.1016/j.immuni.2005.09.015.
  133. Espen S. Baekkevold; Myriam Roussigne; Takeshi Yamanaka; Finn-Eirik Johansen; Frode L. Jahnsen; François Amalric; Per Brandtzaeg; Monique Erard; Guttorm Haraldsen; Jean-Philippe Girard; et al. Molecular Characterization of NF-HEV, a Nuclear Factor Preferentially Expressed in Human High Endothelial Venules. The American Journal of Pathology 2003, 163, 69-79, 10.1016/s0002-9440(10)63631-0.
  134. Corinne Cayrol; Jean-Philippe Girard; IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Current Opinion in Immunology 2014, 31, 31-37, 10.1016/j.coi.2014.09.004.
  135. Rahul Kakkar; Hillary Hei; Stephan Dobner; Richard T. Lee; Interleukin 33 as a Mechanically Responsive Cytokine Secreted by Living Cells*. Journal of Biological Chemistry 2012, 287, 6941-6948, 10.1074/jbc.M111.298703.
  136. Derek E. Byers; Jennifer Alexander-Brett; Anand C. Patel; Eugene Agapov; Geoffrey Dang-Vu; Xiaohua Jin; Kangyun Wu; Yingjian You; Yael Alevy; Jean-Philippe Girard; et al. Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease.. Journal of Clinical Investigation 2013, 123, 3967-3982, 10.1172/JCI65570.
  137. Daniel R. Neill; See Heng Wong; Agustin Bellosi; Robin J. Flynn; Maria Daly; Theresa K. A. Langford; Christine Bucks; Colleen M. Kane; Padraic G. Fallon; Richard Pannell; et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 2010, 464, 1367-1370, 10.1038/nature08900.
  138. Jennifer Kearley; Jonathan S. Silver; Caroline Sanden; Zheng Liu; Aaron A. Berlin; Natalie White; Michiko Mori; Tuyet-Hang Pham; Christine K. Ward; Gerard J. Criner; et al. Cigarette Smoke Silences Innate Lymphoid Cell Function and Facilitates an Exacerbated Type I Interleukin-33-Dependent Response to Infection. Immunity 2015, 42, 566-579, 10.1016/j.immuni.2015.02.011.
  139. Mousa Komai‐Koma; Damo Xu; Yubin Li; Andrew N. J. McKenzie; Iain B. McInnes; Foo Y. Liew; IL-33 is a chemoattractant for human Th2 cells. European Journal of Immunology 2007, 37, 2779-2786, 10.1002/eji.200737547.
  140. Matthew A. Rank; Takao Kobayashi; Hideaki Kozaki; Kathleen R. Bartemes; Diane L. Squillace; Hirohito Kita; IL-33-activated dendritic cells induce an atypical TH2-type response.. Journal of Allergy and Clinical Immunology 2009, 123, 1047-1054, 10.1016/j.jaci.2009.02.026.
  141. Joseph C. Sun; Averil Ma; Lewis L. Lanier; Cutting edge: IL-15-independent NK cell response to mouse cytomegalovirus infection.. The Journal of Immunology 2009, 183, 2911-2914, 10.4049/jimmunol.0901872.
  142. Elvire Bourgeois; Linh Pham Van; Michel Samson; Séverine Diem; Anne Barra; Stéphane Roga; Jean-Marc Gombert; Elke Schneider; Michel Dy; Pierre Gourdy; et al. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-γ production. European Journal of Immunology 2009, 39, 1046-1055, 10.1002/eji.200838575.
  143. Daniel O. Villarreal; David B. Weiner; Interleukin 33: a switch-hitting cytokine.. Current Opinion in Immunology 2014, 28, 102-106, 10.1016/j.coi.2014.03.004.
  144. W. V. Bonilla; K. Senn; S. Kallert; M. Fernández; S. Johnson; M. Kreutzfeldt; A. N. Hegazy; C. Schrick; Padraic Fallon; R. Klemenz; et al. The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses. Science 2012, 335, 984-989, 10.1126/science.1215418.
  145. Lia Ginaldi; Massimo De Martinis; Salvatore Saitta; Maria Maddalena Sirufo; Carmen Mannucci; Marco Casciaro; Fedra Ciccarelli; Sebastiano Gangemi; Interleukin-33 serum levels in postmenopausal women with osteoporosis.. Scientific Reports 2019, 9, 3786, 10.1038/s41598-019-40212-6.
  146. E. A. Carswell; L. J. Old; R. L. Kassel; S. Green; N. Fiore; B. Williamson; An endotoxin-induced serum factor that causes necrosis of tumors.. Proceedings of the National Academy of Sciences 1975, 72, 3666-3670, 10.1073/pnas.72.9.3666.
  147. Tong Zhou; John D Mountz; Robert P Kimberly; Immunobiology of Tumor Necrosis Factor Receptor Superfamily. Immunologic Research 2002, 26, 323-336, 10.1385/ir:26:1-3:323.
  148. Roy A. Black; Charles T. Rauch; Carl J. Kozlosky; Jacques J. Peschon; Jennifer L. Slack; Martin F. Wolfson; Beverly J. Castner; Kim L. Stocking; Pranitha Reddy; Subhashini Srinivasan; et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 1997, 385, 729-733, 10.1038/385729a0.
  149. Wen-Ming Chu; Tumor necrosis factor.. Cancer Letters 2012, 328, 222-225, 10.1016/j.canlet.2012.10.014.
  150. Hana Zelová; Jan Hošek; TNF-α signalling and inflammation: interactions between old acquaintances. Inflammation Research 2013, 62, 641-651, 10.1007/s00011-013-0633-0.
  151. M Grell; Tumor necrosis factor (TNF) receptors in cellular signaling of soluble and membrane-expressed TNF.. Journal of Inflammation 1995, 47, 8–17, https://www.ncbi.nlm.nih.gov/pubmed/8913925.
  152. Daniel Tracey; Lars Klareskog; Eric H. Sasso; Jochen G. Salfeld; Paul P. Tak; Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacology & Therapeutics 2008, 117, 244-279, 10.1016/j.pharmthera.2007.10.001.
  153. Jr Bradley; John Bradley; TNF-mediated inflammatory disease. The Journal of Pathology 2008, 214, 149-160, 10.1002/path.2287.
  154. Yechen Xiao; Hongling Li; Jun Zhang; Andrew Volk; Shubin Zhang; Wei Wei; Shanshan Zhang; Peter Breslin; Jiwang Zhang; TNF-α/Fas-RIP-1–induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations. Blood 2011, 118, 6057-6067, 10.1182/blood-2011-06-359448.
  155. Amy Tsurumi; Yok-Ai Que; Colleen M. Ryan; Ronald G. Tompkins; Laurence G. Rahme; TNF-α/IL-10 Ratio Correlates with Burn Severity and May Serve as a Risk Predictor of Increased Susceptibility to Infections. Frontiers in Public Health 2016, 4, 216, 10.3389/fpubh.2016.00216.
  156. S. Spielmann; T. Kerner; O. Ahlers; D. Keh; M. Gerlach; H. Gerlach; Early detection of increased tumour necrosis factor alpha (TNFalpha) and soluble TNF receptor protein plasma levels after trauma reveals associations with the clinical course.. Acta Anaesthesiologica Scandinavica 2001, 45, 364-370, 10.1034/j.1399-6576.2001.045003364.x.
  157. Olav Reikeras; Pål Borgen; Activation of Markers of Inflammation, Coagulation and Fibrinolysis in Musculoskeletal Trauma. PLOS ONE 2014, 9, e107881, 10.1371/journal.pone.0107881.
  158. Kevin J. Tracey; Yuman Fong; David G. Hesse; Kirk R. Manogue; Annette T. Lee; George C. Kuo; Stephen F. Lowry; Anthony Cerami; Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987, 330, 662-664, 10.1038/330662a0.
  159. K S Mark; W J Trickler; D W Miller; Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells.. Journal of Pharmacology and Experimental Therapeutics 2001, 297, 1051–1058, https://www.ncbi.nlm.nih.gov/pubmed/11356928.
  160. Corinne Van Kampen; Bonnie A Mallard; Regulation of bovine intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) on cultured aortic endothelial cells.. Veterinary Immunology and Immunopathology 2001, 79, 129-138, 10.1016/s0165-2427(01)00251-3.
  161. Veit M. Stoecklein; Akinori Osuka; James A. Lederer; Trauma equals danger--damage control by the immune system.. Journal of Leukocyte Biology 2012, 92, 539-551, 10.1189/jlb.0212072.
  162. Lucia S. Yoshida; Shohko Tsunawaki; Expression of NADPH oxidases and enhanced H2O2-generating activity in human coronary artery endothelial cells upon induction with tumor necrosis factor-α. International Immunopharmacology 2008, 8, 1377-1385, 10.1016/j.intimp.2008.05.004.
  163. B Beutler; I. Milsark; A. Cerami; Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985, 229, 869-871, 10.1126/science.3895437.
  164. Klaus Pfeffer; Toshifumi Matsuyama; Thomas M. Kündig; Andrew Wakeham; Kenji Kishihara; Arda Shahinian; Katja Wiegmann; Pamela S. Ohashi; Martin Krönke; Tak W. Mak; et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993, 73, 457-467, 10.1016/0092-8674(93)90134-c.
  165. Chantal Parent; Andre Kalil; Claire Esposito; Steven M. Banks; Eric P. Gerstenberger; Yvonne Fitz; Robert L. Danner; Charles Natanson; Peter Q. Eichacker; Xizhong Cui; et al. Risk and the Efficacy of Antiinflammatory Agents. American Journal of Respiratory and Critical Care Medicine 2002, 166, 1197-1205, 10.1164/rccm.200204-302oc.
  166. Kamaludin Dingle; Fawaz Azizieh; Multivariate Comparison of Cytokine Profiles for Normal- and Low-Bone-Density Subjects.. Diagnostics 2019, 9, 134, 10.3390/diagnostics9040134.
  167. Tiantian Wang; Chengqi He; TNF-α and IL-6: the link between immune and bone system.. Current Drug Targets 2019, 20, 1-1, 10.2174/1389450120666190821161259.
  168. Tiantian Wang; Chengqi He; Xijie Yu; Chengqi He And Xijie Yu Tiantian Wang; Pro-Inflammatory Cytokines: New Potential Therapeutic Targets for Obesity-Related Bone Disorders. Current Drug Targets 2017, 18, 1664–1675, 10.2174/1389450118666170104153512.
  169. Jung Sun Lee; Doo-Ho Lim; Ji Seon Oh; Yong-Gil Kim; Chang-Keun Lee; Bin Yoo; Seokchan Hong; Effect of TNF inhibitors on bone mineral density in rheumatoid arthritis patients receiving bisphosphonate: a retrospective cohort study.. Rheumatology International 2019, no, no, 10.1007/s00296-019-04418-1.
  170. Masahiro Tada; Kentaro Inui; Yuko Sugioka; Kenji Mamoto; Tadashi Okano; Shohei Anno; Tatsuya Koike; Use of bisphosphonate might be important to improve bone mineral density in patients with rheumatoid arthritis even under tight control: the TOMORROW study. Rheumatology International 2017, 37, 999-1005, 10.1007/s00296-017-3720-7.
  171. Teun J. De Vries; Ismail El Bakkali; Thomas Kamradt; Georg Schett; Ineke D. C. Jansen; Patrizia D'amelio; What Are the Peripheral Blood Determinants for Increased Osteoclast Formation in the Various Inflammatory Diseases Associated With Bone Loss?. Frontiers in Immunology 2019, 10, 505, 10.3389/fimmu.2019.00505.
  172. D. F. Fiorentino; Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. The Journal of Experimental Medicine 1989, 170, 2081-2095, 10.1084/jem.170.6.2081.
  173. Alexander Zdanov; Céline Schalk-Hihi; Alla Gustchina; Monica Tsang; James Weatherbee; Alexander Wlodawer; Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon γ. Structure 1995, 3, 591-601, 10.1016/s0969-2126(01)00193-9.
  174. Jacques Banchereau; Virginia Pascual; Anne O'garra; From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nature Immunology 2012, 13, 925-931, 10.1038/ni.2406.
  175. Ram Savan; Sarangan Ravichandran; Jack R. Collins; Masahiro Sakai; Howard A. Young; Structural conservation of interferon gamma among vertebrates. Cytokine & Growth Factor Reviews 2009, 20, 115-124, 10.1016/j.cytogfr.2009.02.006.
  176. Lisa Siewe; Mariela Bollati–Fogolin; Claudia Wickenhauser; Thomas Krieg; Werner Müller; Axel Roers; Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA. European Journal of Immunology 2006, 36, 3248-3255, 10.1002/eji.200636012.
  177. Samuel Huber; Nicola Gagliani; Enric Esplugues; William O'connor; Francis J. Huber; Ashutosh Chaudhry; Masahito Kamanaka; Yasushi Kobayashi; Carmen J. Booth; Alexander Y. Rudensky; et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner.. Immunity 2011, 34, 554-565, 10.1016/j.immuni.2011.01.020.
  178. Robert Sabat; Gerald Grutz; Katarzyna Warszawska; Stefan Kirsch; Ellen Witte; Kerstin Wolk; Jens Geginat; Biology of interleukin-10. Cytokine & Growth Factor Reviews 2010, 21, 331-344, 10.1016/j.cytogfr.2010.09.002.
  179. Serguei V. Kotenko; Christopher D. Krause; Lara S. Izotova; Brian P. Pollack; Wei Wu; Sidney Pestka; Identification and functional characterization of a second chain of the interleukin-10 receptor complex.. The EMBO Journal 1997, 16, 5894-5903, 10.1093/emboj/16.19.5894.
  180. S. I. Yoon; N. J. Logsdon; F. Sheikh; Raymond Donnelly; M. R. Walter; Conformational Changes Mediate Interleukin-10 Receptor 2 (IL-10R2) Binding to IL-10 and Assembly of the Signaling Complex. Journal of Biological Chemistry 2006, 281, 35088-35096, 10.1074/jbc.m606791200.
  181. Luca Crepaldi; Sara Gasperini; José A. Lapinet; Federica Calzetti; Cristina Pinardi; Ying Liu; Sandra Zurawski; René De Waal Malefyt; Kevin W. Moore; Marco A. Cassatella; et al. Up-regulation of IL-10R1 expression is required to render human neutrophils fully responsive to IL-10.. The Journal of Immunology 2001, 167, 2312-2322, 10.4049/jimmunol.167.4.2312.
  182. Marina C. Pils; Fabio Pisano; Nicolas Fasnacht; Jan-Michael Heinrich; Lothar Groebe; Angela Schippers; Björn Rozell; Robert S. Jack; Werner Müller; Monocytes/macrophages and/or neutrophils are the target of IL-10 in the LPS endotoxemia model. European Journal of Immunology 2010, 40, 443-448, 10.1002/eji.200939592.
  183. Faruk Sheikh; Vitaliy V. Baurin; Anita Lewis-Antes; Nital K. Shah; Sergey V. Smirnov; Shubha Anantha; Harold Dickensheets; Laure Dumoutier; Jean-Christophe Renauld; Alexander Zdanov; et al. Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2.. The Journal of Immunology 2004, 172, 2006-2010, 10.4049/jimmunol.172.4.2006.
  184. Matthew R. Jones; Lee J. Quinton; Benjamin T. Simms; Michal M. Lupa; Mariya S. Kogan; Joseph P. Mizgerd; Roles of interleukin-6 in activation of STAT proteins and recruitment of neutrophils during Escherichia coli pneumonia.. The Journal of Infectious Diseases 2005, 193, 360-369, 10.1086/499312.
  185. D S Finbloom; K D Winestock; IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes.. The Journal of Immunology 1995, 155, 1079-1090, https://www.jimmunol.org/content/155/3/1079.short.
  186. Antje K. Kretzschmar; Michaela C. Dinger; Christian Henze; Katja Brocke-Heidrich; Friedemann Horn; Analysis of Stat3 (signal transducer and activator of transcription 3) dimerization by fluorescence resonance energy transfer in living cells. Biochemical Journal 2004, 377, 289-297, 10.1042/bj20030708.
  187. Shouval, D.S.; Ouahed, J.; Biswas, A.; Goettel, J.A.; Horwitz, B.H.; Klein, C.; Muise, A.M.; Snapper, S.B. Interleukin 10 Receptor Signaling. In Advances in Immunology; Elsevier: Amsterdam, The Netherlands, 2014; Volume 122, pp. 177–210.
  188. Mechthild Jung; Robert Sabat; Jörn Krätzschmar; Henrik Seidel; Kerstin Wolk; Christiane Schönbein; Sabine Schütt; Markus Friedrich; Wolf-Dietrich Döcke; Khusru Asadullah; et al. Expression profiling of IL-10-regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL-10 therapy. European Journal of Immunology 2004, 34, 481-493, 10.1002/eji.200324323.
  189. Daiana Martire-Greco; Nahuel Rodriguez-Rodrigues; Verónica I. Landoni; Barbara Rearte; Martín A. Isturiz; Gabriela C. Fernández; Interleukin-10 controls human peripheral PMN activation triggered by lipopolysaccharide. Cytokine 2013, 62, 426-432, 10.1016/j.cyto.2013.03.025.
  190. Olivier Huet; E. Laemmel; Y. Fu; L. Dupic; A. Aprico; K.L. Andrews; X.L. Moore; A. Harrois; P.L. Meikle; E. Vicaut; et al. IL-10 anti oxidant effect decreases leukocytes/ endothelial interaction induced by TNF-α. Shock 2013, 39, 83-88, 10.1097/shk.0b013e318278ae36.
  191. Jacques Thibodeau; Marie-Claude Bourgeois-Daigneault; Gabrielle Huppé; Jessy Tremblay; Angélique Aumont; Mathieu Houde; Eric Bartee; Alexandre Brunet; Marie-Elaine Gauvreau; Aude De Gassart; et al. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes.. European Journal of Immunology 2008, 38, 1225-1230, 10.1002/eji.200737902.
  192. Vicioso, M.A.; Garaud, J.J.; Réglier-Poupet, H.; Lebeaut, A.; Gougerot-Pocidalo, M.A.; Chollet-Martin, S. Moderate inhibitory effect of interleukin-10 on human neutrophil and monocyte chemotaxis in vitro. Eur. Cytokine Netw. 1998, 9, 247–253.
  193. Gautam Sikka; Karen L. Miller; Jochen Steppan; Deepesh Pandey; Sung M. Jung; Charles D. Fraser; Carla Ellis; Daniel Ross; Koenraad Vandegaer; Djahida Bedja; et al. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age.. Experimental Gerontology 2012, 48, 128-135, 10.1016/j.exger.2012.11.001.
  194. Nadine Koch; Mechthild Jung; Robert Sabat; Jörn Krätzschmar; Wolf-Dietrich Döcke; Khusru Asadullah; Hans-Dieter Volk; Gerald Grütz; IL-10 protects monocytes and macrophages from complement-mediated lysis. Journal of Leukocyte Biology 2009, 86, 155-166, 10.1189/jlb.0708443.
  195. Ralf Kühn; Jürgen Löhler; Donna Rennick; Klaus Rajewsky; Werner Müller; Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993, 75, 263-274, 10.1016/0092-8674(93)80068-p.
  196. Satoshi Ito; Parswa Ansari; Minoru Sakatsume; Harold Dickensheets; Nancy Vazquez; Raymond P. Donnelly; Andrew C. Larner; David S. Finbloom; Interleukin-10 Inhibits Expression of Both Interferon – and Interferon γ– Induced Genes by Suppressing Tyrosine Phosphorylation of STAT1. Blood 1999, 93, 1456-1463, 10.1182/blood.v93.5.1456.
  197. Y. Heper; E. H. Akalın; R. Mıstık; S. Akgoz; O. Tore; G. Göral; B. Oral; F. Budak; S. Helvacı; Haluk Barbaros Oral; et al. Evaluation of serum C-reactive protein, procalcitonin, tumor necrosis factor alpha, and interleukin-10 levels as diagnostic and prognostic parameters in patients with community-acquired sepsis, severe sepsis, and septic shock. European Journal of Clinical Microbiology & Infectious Diseases 2006, 25, 481-491, 10.1007/s10096-006-0168-1.
  198. A. Marchant; M. L. Alegre; A. Hakim; G. Piérard; G. Marecaux; G. Friedman; D. De Groote; R. J. Kahn; J. L. Vincent; M. Goldman; et al. Clinical and biological significance of interleukin-10 plasma levels in patients with septic shock. Journal of Clinical Immunology 1995, 15, 266-273, 10.1007/bf01540884.
  199. Regula Neidhardt; Marius Keel; Ursula Steckholzer; Alexandra Safret; Udo Ungethuem; Otmar Trentz; Wolfgang Ertel; Relationship of interleukin-10 plasma levels to severity of injury and clinical outcome in injured patients.. The Journal of Trauma: Injury, Infection, and Critical Care 1997, 42, 863-871, 10.1097/00005373-199705000-00017.
  200. Richard M. Sherry; Jorge I. Cué; Julie K. Goddard; James B. Parramore; Joseph T. DiPiro; Interleukin-10 Is Associated with the Development of Sepsis in Trauma Patients. The Journal of Trauma: Injury, Infection, and Critical Care 1996, 40, 613-616, 10.1097/00005373-199604000-00016.
  201. Naiomy D. Rios‐Arce; Andrew Dagenais; Derrick Feenstra; Brandon Coughlin; Ho Jun Kang; Susanne Mohr; Laura R. McCabe; Narayanan Parameswaran; Loss of interleukin-10 exacerbates early Type-1 diabetes-induced bone loss.. Journal of Cellular Physiology 2019, no, no, 10.1002/jcp.29141.
  202. Wang, T.; Jiang, C.; Zhao, P.; Chen, L.; Li, Z.; Detection and analysis of serum IL-10 and TGF-beta1 in the SLE patients with osteoporosis or osteonecrosis. Chinese Journal of Cellular and Molecular Immunology 2018, 34, 1032-1035, https://europepmc.org/article/med/30591113.
  203. Marco Baggiolini; Ian Clark-Lewis; Interleukin-8, a chemotactic and inflammatory cytokine. FEBS Letters 1992, 307, 97-101, 10.1016/0014-5793(92)80909-z.
  204. Valentino Bezzerri; Monica Borgatti; Alessia Finotti; Anna Tamanini; Roberto Gambari; Giulio Cabrini; Mapping the Transcriptional Machinery of the IL-8 Gene in Human Bronchial Epithelial Cells. The Journal of Immunology 2011, 187, 6069-6081, 10.4049/jimmunol.1100821.
  205. Hoffmann, E.; Dittrich-Breiholz, O.; Holtmann, H.; Kracht, M.; Multiple control of interleukin-8 gene expression. J. Leukoc. Biol. 2002, 72, 847–855, 10.1189/jlb.72.5.847.
  206. Manfred Lehner; Patrick Morhart; Andrea Stilper; Dagmar Petermann; Perdita Weller; Daniel Stachel; Wolfgang Holter; Efficient Chemokine-dependent Migration and Primary and Secondary IL-12 Secretion by Human Dendritic Cells Stimulated Through Toll-like Receptors. Journal of Immunotherapy 2007, 30, 312-322, 10.1097/01.cji.0000211345.11707.46.
  207. Johanna Hol; Axel M. Küchler; Finn-Eirik Johansen; Bjørn Dalhus; Guttorm Haraldsen; Inger Øynebråten; Molecular Requirements for Sorting of the Chemokine Interleukin-8/CXCL8 to Endothelial Weibel-Palade Bodies*. Journal of Biological Chemistry 2009, 284, 23532-23539, 10.1074/jbc.M900874200.
  208. Akhil Maheshwari; Nikolai N. Voitenok; Svetlana Akalovich; Sadiq S. Shaik; David A. Randolph; Brian Sims; Rakesh P. Patel; Cheryl R. Killingsworth; Michael B. Fallon; Robin K. Ohls; et al. Developmental changes in circulating IL-8/CXCL8 isoforms in neonates.. Cytokine 2009, 46, 12-16, 10.1016/j.cyto.2008.12.022.
  209. Irundika H. K. Dias; Lindsay Marshall; Peter A. Lambert; Iain L. C. Chapple; John B. Matthews; Helen R. Griffiths; Gingipains from Porphyromonas gingivalis Increase the Chemotactic and Respiratory Burst-Priming Properties of the 77-Amino-Acid Interleukin-8 Variant▿. Infection and Immunity 2007, 76, 317-323, 10.1128/IAI.00618-07.
  210. Ravi Ramjeesingh; Randy Leung; Chi-Hung Siu; Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1. The FASEB Journal 2003, 17, 1292-1294, 10.1096/fj.02-0560fje.
  211. Timothy Craig Allen; Anna Kurdowska; Interleukin 8 and Acute Lung Injury. Archives of Pathology & Laboratory Medicine 2014, 138, 266-269, 10.5858/arpa.2013-0182-ra.
  212. Kurdowska, A.; Noble, J.M.; Steinberg, K.P.; Ruzinski, J.T.; Hudson, L.D.; Martin, T.R. Anti-interleukin 8 autoantibody: Interleukin 8 complexes in the acute respiratory distress syndrome. Relationship between the complexes and clinical disease activity. Am. J. Respir. Crit. Care Med. 2001, 163, 463–468.
  213. Yoshiro Kobayashi; The role of chemokines in neutrophil biology.. Frontiers in Bioscience 2008, 13, 2400-2407, 10.2741/2853.
  214. Yan Ning; Philipp C. Manegold; Young Kwon Hong; Wu Zhang; Alexandra Pohl; Georg Lurje; Thomas Winder; Ngyun Yang; Melissa J. LaBonte; Peter M. Wilson; et al. Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models.. International Journal of Cancer 2011, 128, 2038-2049, 10.1002/ijc.25562.
  215. Aihua Li; Seema Dubey; Michelle L. Varney; Bhavana J. Dave; Rakesh K. Singh; IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis.. The Journal of Immunology 2003, 170, 3369-3376, 10.4049/jimmunol.170.6.3369.
  216. Robert Kraft; David N. Herndon; Celeste C. Finnerty; Robert A. Cox; Juquan Song; Marc G. Jeschke; Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study.. SHOCK 2015, 43, 222-227, 10.1097/SHK.0000000000000294.
  217. Stephen P. J. Macdonald; Shelley F. Stone; Claire L. Neil; Pauline E. Van Eeden; Daniel M. Fatovich; Glenn Arendts; Simon G. A. Brown; Sustained Elevation of Resistin, NGAL and IL-8 Are Associated with Severe Sepsis/Septic Shock in the Emergency Department. PLOS ONE 2014, 9, e110678, 10.1371/journal.pone.0110678.
  218. Luiz Carlos Brasiliano Ferreira; Andrea Regner; Karen Dal Lago Miotto; Silvana De Moura; Nilo Ikuta; Andréia Escosteguy Vargas; José Artur Bogo Chies; Daniel Simon; Increased levels of interleukin-6, -8 and -10 are associated with fatal outcome following severe traumatic brain injury. Brain Injury 2014, 28, 1311-1316, 10.3109/02699052.2014.916818.
  219. Aleksandar Gopcevic; Branka Mazul-Sunko; Jasminka Marout; Ante Sekulic; Natasa Antoljak; Mladen Siranovic; Zeljko Ivanec; Marko Margaritoni; Miroslav Bekavac-Beslin; Neven Zarkovic; et al. Plasma interleukin-8 as a potential predictor of mortality in adult patients with severe traumatic brain injury.. The Tohoku Journal of Experimental Medicine 2007, 211, 387-393, 10.1620/tjem.211.387.
  220. Nasser M Al-Daghri; Sobhy Yakout; Eman Al-Shehri; Hanan A Al-Fawaz; Naji Aljohani; Yousef Al-Saleh; Inflammatory and bone turnover markers in relation to PTH and vitamin D status among saudi postmenopausal women with and without osteoporosis. International journal of clinical and experimental medicine 2014, 7, 3528-3535, PMC4238474.
  221. Luzia Hermínia Sousa; Eveline V. M. Linhares; Joanna Trycia Alexandre; Mario Roberto Lisboa; Flávia Furlaneto; Raul Freitas; Isabela Ribeiro; Danielle Val; Mirna Marques; Hellíada Vasconcelos Chaves; et al. Effects of Atorvastatin on Periodontitis of Rats Subjected to Glucocorticoid-Induced Osteoporosis. Journal of Periodontology 2016, 87, 1206-1216, 10.1902/jop.2016.160075.
  222. Xiaoling Hu; Yongchang Sun; Weihan Xu; Tao Lin; Hui Zeng; Expression of RANKL by peripheral neutrophils and its association with bone mineral density in COPD. Respirology 2016, 22, 126-132, 10.1111/resp.12878.
  223. Hu, X.; Sun, Y.; Xu, W.; Lin, T.; Zeng, H.; Expression of RANKL by peripheral neutrophils and its association with bone mineral density in COPD. Respirology 2017, 22, 126–132, https://www.nejm.org/doi/10.1056/NEJMra1208623.
  224. Angus, D.C.; van der Poll, T.; Severe sepsis and septic shock. N. Engl. J. Med 2013, 369, 2063, https://www.nejm.org/doi/10.1056/NEJMra1208623.
  225. Daniel Rittirsch; Michael A. Flierl; Peter A. Ward; Harmful molecular mechanisms in sepsis. Nature Reviews Immunology 2008, 8, 776-787, 10.1038/nri2402.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback