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Interleukin-18 Binding Protein Autoimmune Diseases
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10071750

Natural soluble antagonist and decoy receptor on the surface of the cell membrane are evolving as crucial immune system regulators as these molecules are capable of recognizing, binding, and neutralizing (so-called inhibitors) their targeted ligands. Eventually, these soluble antagonists and decoy receptors terminate signaling by prohibiting ligands from connecting to their receptors on the surface of cell membrane. Interleukin-18 binding protein (IL-18BP) participates in regulating both Th1 and Th2 cytokines. IL-18BP is a soluble neutralizing protein belonging to the immunoglobulin (Ig) superfamily as it harbors a single Ig domain. The Ig domain is essential for its binding to the IL-18 ligand and holds partial homology to the IL-1 receptor 2 (IL-1R2) known as a decoy receptor of IL-1α and IL-1β. IL-18BP was defined as a unique soluble IL-18BP that is distinct from IL-18Rα and IL-18Rβ chain. IL-18BP is encoded by a separated gene, contains 8 exons, and is located at chr.11 q13.4 within the human genome.

IL-18BP Th1/Th2 balance autoimmune diseases

1. Regulation of IL-18BP

Interleukin-18 (IL-18) was discovered in 1995 as a novel interferon-γ (IFNγ) inducing factor (IGIF), and later it was named IL-18 (also known as IL-1F4) due to the amino acid sequence homology with IL-1β as well as sharing the processing enzyme, caspase-1. Moreover, IL-18 induces IFNγ, including other proinflammatory cytokines in the immune response to pathogens or cell damage. These danger inducements contact cell surface through pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which in turn bind to the Toll-like receptors (TLR). Then, the activated TLRs trigger myeloid differentiation factor 88 (MyD88) and allow it to make a complex with the interleukin-1 receptor-associated kinase (IRAK) as well as TNF receptor-associated factor (TRAF). This signaling pathway results in oligomerization of inflammasome, and consequently, caspase-1 becomes activated. On the other hand, the translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) induces several proinflammatory cytokines, including pro-interleukin IL-18 (pro-IL-18). The activated caspase is proteolytically cleaved and activates pro-IL-18 to be released from the cell as its mature form; IL-18. First, secreted IL-18 binds to the IL-18 receptor alpha chain (IL-18Rα), then recruits the IL-18 receptor beta chain (IL-18Rβ) to initiate the signaling pathway. IL-18 signaling cascades elicited the activation of mitogen-activated protein kinases (MAPKs) and NF-κB, which in turn led to IFNγ and numerous inflammatory gene expressions and enabled continuous loop activation, as the binding of IL-18 to its receptor acts as a downstream activation for NF-κB) [1][2][3][4][5][6][7][8].
IL-18 binding protein (IL-18BP) is a natural soluble antagonist, and it binds to the IL-18 ligand with a high affinity. This high-affinity binding of IL-18BP sufficiently blocks the interaction of IL-18 with the IL-18Rα ligand-binding chain on the cell surface and eventually inhibits the IL-18 signaling pathway. Therefore, IL-18BP is considered a potent IL-18 inhibitor. Furthermore, the production of IFNγ induces IL-18BP to be present as a control role under the term of negative feedback, and IL-18BP is found to be expressed in various organs, such as the spleen, small intestine, stomach, colon, placenta, and lung [7][8][9][10][11][12][13]. This is not surprising, as IL-18 was first described as an IFNγ inducing factor (IGIF) [14], and increasing evidence showed that IL-18 induces IFNγ under various conditions [2][15][16][17]. Notably, IL-18BP was found extracellularly and in 20-folds higher than IL-18 level in healthy sera, which conveys its important regulatory maintenance function [7][18][19][20]. Given that IL-18BP is constitutively expressed from various organs/tissues and secreted into the blood in which it is not anchored on the cell membrane. IL-18BP lacks a transmembrane domain; therefore, it acts as a local as well as systemic IL-18 feedback regulation. As a result, it reduces IFNγ production, avoiding the harmful effect of prolonged inflammatory reactions.
Both IL-18 and IL-18BP occupied a location within chromosome 11 in human genomes. However, each has a distinct cytoband location, q23.1 and q13, respectively [21]. Additionally, the IL-18BP promoter was found to hold several response elements that are required for basal activity. Among them, one site of IFN regulatory factor 1 response element (IRF-E), one site of signal transducer and activator of transcription 1 (STAT1), and two sites of CCAAT-enhancer binding protein beta (CEBP-β), all play a significant role in direct IL-18BP activation in several cell types [12][22]. Based on the existence of these transcription factors, some reports discovered an unexpected expression for IL-18BP irrespective of the presence of IL-18, such as its association with IL-27 [23]. It was found that IL-27 induces the mRNA transcription level as well as the secretion of IL-18BP protein level in a dose-dependent manner. This was accomplished through IL-27-mediated STAT1 activation, which in turn binds to the Gamma-activated sequence (GAS) element within the promoter of IL-18BP, and thus regulates its expression.
Moreover, this transcriptional activation of the IL-18BP promoter regulates the IL-18BP expression by IFNγ and other different stimuli [12][24][25]. Notably, the IL-18BP induction was enhanced specifically upon IFNγ, while the levels of the induction varied between monocytes and epithelial cells. These IFNγ induced IL-18BP variation levels were controlled epigenetically through CpG methylation on the promoter region. Therefore, they were diminished in monocytes as the promoter CpG was found to be methylated in contrast to unmethylated in epithelial cells [26]. As a result, not only CpG methylation, but also other epigenetic modifications can draw the specificity of IL-18BP related to cell types, which is still waiting to be investigated.

2. Difference in the Biological Activity of IL-18BP Isoforms

Initially, IL-18BP was discovered in 1999 by the IL-18 ligand affinity chromatographic analysis while looking for a soluble form of IL-18 receptor-ligand binding chain using concentrated human urine as a source of body fluid proteins [7][18][19][20]. It was defined as a unique soluble protein that is distinct from IL-18Rα and IL-18Rβ chain. IL-18BP is encoded by a separated gene and contains 8 exons. The protein encoded by the IL-18BP gene translated into four isoforms in humans. As previously mentioned, IL-18BP is a soluble neutralizing protein belonging to the immunoglobulin (Ig) superfamily as it harbors a single Ig domain. The Ig domain is essential for its binding to the IL-18 ligand and holds partial homology to the IL-1 receptor 2 (IL-1R2), which is known as a decoy receptor of IL-1α and IL-1β. Among them, two isoforms were found to be active, IL-18BPa and IL-18BPc, since both hold the complete Ig domain. However, their binding affinities to the IL-18 are distinct. IL-18BPa showed an 18 times higher affinity to the IL-18 than IL-18BPc, this is predominantly due to the C-terminal difference. While, on the other hand, IL-18BPb and IL-18BPd lack the essential Ig domain, and thus show no activity in sequestering IL-18. As a result, no inhibition of the IL-18 signal pathway occur [4][5][6][7]. Furthermore, the sequence differences between isoforms point toward different post translational modifications (PTM). Although IL-18BP was reported as a heavily glycosylated protein, isoform b (O95998-3) showed missing conserved amino acids for PTMs. While the two closer isoforms, IL-18BPa and IL-18BPc (O95998, and G3V1C5), hold amino acids for all available PTMs, which are three sites for N-linked glycosylation, site for O-linked glycosylation, and the cysteines for two disulfide bridges. These modifications may play a key role in the activity of the respective protein/isoform, which also might acknowledge the less or no activity for isoforms other than IL-18BPa. In addition, the amino acid sequence of IL-37 was reported to have some similarity with IL-18 within the binding motif. Therefore, it was suggested that IL-37 might bind to IL-18 receptors and IL-18BP. Yet, these binding and their consequent effect still require additional investigation [27].

3. IL-18BP in Autoimmune Diseases

IL-18/IL-18BP imbalance is highly linked to immunologically mediated diseases, especially diseases that have a pathological role of IFNγ, such as macrophage activated syndrome (MAS) [2][28][29][30][31][32][33]. MAS is a life-threatening condition that is not mainly a syndrome on its own, but is also found to be associated with other infectious and autoinflammatory diseases [2][28][32][34][35][36][37][38][39]. Various infections developed MAS, including Epstein–Barr virus, cytomegalovirus, and herpes virus, and infections with other pathogens, such as intracellular bacteria and parasites, as well as numerous lymphomas [28][29][30][31][32]. Moreover, MAS could be present as a form of secondary hemophagocytic lymphohistiocytosis (HLH), in addition to the rare and serious rheumatic diseases, such as adult-onset Still’s disease (AOSD) and its counterpart in children and systemic juvenile idiopathic arthritis (sJIA) [33][40][41][42][43][44]. In both conditions, secondary HLH and AOSD/sJIA, a significant elevation of IL-18 was validated and found to be correlated to disease activity and severity [33][43][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64]. MAS and IL-18 serum levels both represent the shared pathogenic features between these two different disease conditions. Under active MAS, IL-18 induces T cells expansion, and thus enhances the production of IFNγ and antigen-presenting cells (APCs) activation, predominantly dendritic cells (DCs), which in turn support the activation of macrophages. Consequently, this activation results in prolonged activation of these cells along with their inflammatory mediators, such as cytokine storm [45][46][47]. Therefore, increasing evidence showed that MAS-associated AOSD/sJIA had higher levels of IL-18 when compared to patients with no MAS association, IL-18BP or equivalent, which are suggested as a potential therapeutic option to neutralize IL-18 for MAS-associated conditions [34][59][65][66][67].
Tadekinig-α is a human recombinant IL-18BP (rhIL-18BP) with an IL-18 high affinity and has been investigated in two serious inflammatory conditions that are associated with unusual elevation of IL-18 plasma levels; AOSD/sJIA and a refractory HLH bearing a gain of function mutation named NLR family CARD domain containing 4 (NLRC4)-related MAS. To date, promising results showed a favorable response toward Tadekinig-α in AOSD/sJIA and NLRC4-related MAS, which are currently under phase II and III, respectively (ClinicalTrials.gov Identifier: NCT02398435, NCT03113760, NCT03512314) [43][68][69][70]. Notably, in phase II clinical trial on Tadekinig-α, 50% of the AOSD cohort reached normal body temperature and reduced C-reactive protein (CRP) levels within 3 weeks under treatment, confirming the neutralization effect of the free bioactive IL-18 [68]. More recently, a case report revealed undetectable serum levels of the free IL-18 after only 2 h upon first administration of Tadekinig-α, while again increased when the administration of Tadekinig-α was discontinued [69].
MicroRNAs (miRNAs) are known as short non-coding sequences of RNA, which show a repression function. Notably, the reported miRNA (miRNA-134) that targeted IL-18BP, was found to be elevated in AOSD plasma and correlated with the activity of the disease [71]. It is well known that changes in miRNAs are considered as post-transcription gene regulators, and participate in human disorder pathogenesis [72]. Therefore, miRNA-134 can be an AOSD biomarker as well as a target for augmentation therapy. On the other hand, HLH patients carrying the NLRC4 mutation were examined under the Tadekinig-α regimen earlier than AOSD/sJIA, demonstrating a successful treatment in HLH holding NLRC4 genetic background [70][73][74].
Although IL-18/IL-18BP has significantly dysregulated in the abovementioned MAS-associated diseases, the imbalance of IL-18/IL-18BP has also been noticed in other inflammatory diseases, including rheumatoid arthritis (RA), psoriasis, asthma, lupus erythematosus, multiple sclerosis, atherosclerosis, renal and liver injury, inflammatory bowel disease (IBD), Crohn’s disease (CD), organ transplant rejection together with Graft versus host disease (GvHD), and most recently in pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome [15][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89], where cytokine imbalance is a major feature of these autoimmune disorders. The refractory monogenic inflammatory disorder, PAPA, resulted from a dominant mutation with the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) gene and is characterized by acne and skin ulceration. In addition, the autoimmune neutrophilic destruction of joints and skin is the major clinical presentation of PAPA, but it was not associated with MAS [90][91]. Moreover, a recently published study found that IL-18 is elevated in the patient serum and this elevation was highly associated with the disease outcome, again with no MAS risk [89].
Therefore, IL-18 elevation and depletion in IL-18BP function is a biomarker for most of these diseases. However, targeting IL-18 by IL-18BP or equivalent is yet to be fully explored. Humanized IgG1 monoclonal antibody (anti-IL-18), GSK1070806, is instantly in the development phase for treating a variety of inflammatory conditions, atopic dermatitis (AD) and IBD in phase I, delayed graft function, CD, and Behcet’s disease in phase II (ClinicalTrials.gov Identifier: NCT04975438, NCT01035645, NCT02723786, NCT03681067, NCT03522662) [92]. In addition to Tadekinig-α and GSK1070806, a long-acting antibody drug targeting IL-18 and APB-R3 is developed for inflammatory autoimmune disease treatment in preclinical stages, and will soon enter phase I clinical trial [93].
Improving IL-18 targeting by allowing it to act for a longer time or with superior affinity appears to be promising and beneficial, taking into consideration sequence and structural features that affect the binding interaction. A recent structural study aimed to characterize the IL-18BP sequestration mechanism and reveal a novel disulfide-linked boundary, resulting in tetrameric assembly between IL-18BP and IL-18 [94]. During their study, due to N-terminal heavy glycosylation, they produce hIL-18BPΔN, an hIL-18BP that lacks N-terminal residues 63-194 and is treated with Endoglycosidase H. This form has lower glycosylation and still has the disulfide bridge, which shows a comparable IL-18 sequestering ability with high affinity, but at a higher rate. Therefore, hIL-18BPΔN might be a promising IL-18 neutralizing drug.
IL-18 has been involved in the injury of several organs as well as in potentially fatal conditions, which are exemplified by a cytokine storm. Lately, after the emergence of the COVID-19 crisis, heavy-handed cases of SARS CoV-2 infection showed a cytokine storm that derives tissue damage [95][96][97][98]. The COVID-19 mediated cytokine storm showed that elevated IL-18 is one of the cytokines involved in the storm. Moreover, due to its remarkable elevation, IL-18 was recognized as a biomarker for disease severity [95][96][98][99][100]. Therefore, IL-18BP has been suggested as a promising therapy for COVID-19. Yet, there are no pre or clinical trials in this regard [17][101][102]. Furthermore, the lack of proper and well-characterized animal models slows down the movement for further discovering and understanding IL-18BP as a potential therapeutic option for a wide range of disorders.

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Seung Yong Park
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Yasmin Hisham
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Hyun Mu Shin
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Su Cheong Yeom
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Soohyun Kim
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