TGF-β, Activin and Follistatin in Inflammatory Bowel Disease: Comparison
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Inflammatory bowel disease (IBD) is an immune-mediated inflammatory condition predominantly affecting the gastrointestinal (GI) tract. An increasing prevalence of IBD has been observed globally. The pathogenesis of IBD includes a complex interplay between the intestinal microbiome, diet, genetic factors and immune responses. The consequent imbalance of inflammatory mediators ultimately leads to intestinal mucosal damage and defective repair. Growth factors, given their specific roles in maintaining the homeostasis and integrity of the intestinal epithelium, are of particular interest in the setting of IBD. Furthermore, direct targeting of growth factor signalling pathways involved in the regeneration of the damaged epithelium and the regulation of inflammation could be considered as therapeutic options for individuals with IBD. Several members of the transforming growth factor (TGF)-β superfamily, particularly TGF-β, activin and follistatin, are key candidates as they exhibit various roles in inflammatory processes and contribute to maintenance and homeostasis in the GI tract. 

  • TGF-β
  • activin
  • follistatin
  • inflammation

1. Introduction

Inflammatory Bowel Diseases (IBD) are characterised by active, chronic inflammatory changes in the gastrointestinal (GI) tract [1]. IBD may be subtyped into typical forms (Crohn’s disease (CD), ulcerative colitis (UC) or IBD-unclassified (IBDU)) and atypical subtypes (atypical UC, CD colitis) according to features such as disease location and the pattern of inflammation [1,2][1][2].
Although the pathogenesis of these conditions is not fully elucidated, the best accepted hypothesis is that gut inflammation begins in response to key environmental, dietary, microbial and immune responses in an individual at genetic risk [3,4][3][4]. In recent years, the complexity of the innate and acquired immune responses relevant to IBD has been investigated and understanding has expanded substantially.

2. TGF-β

2.1. General Aspects of TGF-β

The TGF-β family is comprised of three homologous peptides: TGF-β1, TGF-β2 and TGF-β3. Of these, TGF-β1 is predominant and plays a major regulatory role in the immune system [10,11][5][6]. In general, the TGF-βs are multifunctional cytokines that contribute to the regulation of several key cellular functions including cell proliferation, differentiation, migration, apoptosis and extracellular matrix production [12][7]. TGF-β is extensively expressed by epithelial cells, fibroblasts and immune cells [13][8]. It acts as a potent inhibitor of cell growth and stimulator of cell differentiation in intestinal epithelial cells [14][9]. TGF-β is a potent chemo-attractant for neutrophils and stimulates epithelial cell migration at wound sites, thus facilitating wound repair. TGF-β also has an inhibitory role that diminishes subsequent inflammatory responses [15][10]. TGF-β promotes class-switching immunoglobulin (Ig)A in both human and mouse B cells and has an inhibitory activity upon the production of antibodies [16][11]. It stimulates resting monocytes, inhibits activated macrophages and acts as a chemoattractant for monocytes [17][12]. Furthermore, it downregulates inflammatory cytokine production by monocytes and macrophages through the inhibition of nuclear factor (NF)-κB [18][13]. Overall, TGF-β maintains the immune balance of the GI tract in three key ways: enhancing mucosal defense, promoting immune tolerance and suppressing anti-inflammatory responses [19][14].

2.2. Biological Roles of TGF-β

The active TGF-β ligand binds to the TGF-β receptor (R)II and initiates TGF-βRII to form a complex with TGF-βRI with the assistance of accessory TGF-βRIII. The TGF-βR complex then mediates transduction of signals through canonical Smad (Smad 2, 3 and 4) and non-canonical pathways [20][15]. In the Smad-dependent canonical pathway, phosphorylated Smad2 and Smad3 form a complex with Smad4 and enter the nucleus to regulate the transcription of target genes [11,21,22][6][16][17]. Smad7 is a downstream target of the TGF-β pathway that negatively regulates TGF-β signalling by competing for Smad3′s binding site on the TGF-β receptor, thereby blocking Smad3 activation [23,24,25][18][19][20]. Suppression of cytokine production by TGF-β is Smad2/3-dependent [26,27][21][22]. The Smad3/4 pathway is also an important mediator of TGF-β signalling in immune regulation. Disruption of Smad4, specifically in T cells, results in colitis and an increased susceptibility to spontaneous development of colorectal tumors [28][23]. It has been noted that Smad3 phosphorylation levels and Smad7 protein levels were markedly reduced and increased respectively in mucosal samples of patients with CD [29,30][24][25]. In these individuals there is marked over-expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and increased production of matrix-degrading enzymes by fibroblasts and macrophages. Simultaneously, endogenous healing pathways mediated by TGF-β are inhibited because mucosal inflammatory cells express Smad7 [31][26]. It has been demonstrated that Smad7 antisense therapy reduced Smad7 protein levels, increased levels of phosphorylated Smad3 and decreased levels of mucosal pro-inflammatory cytokines including TNF-α and interferon (IFN)-γ [29][24]. In addition to the canonical Smad pathway, other signalling pathways, including the extracellular signal-regulated kinases (ERK1/2), mitogen-activated protein kinase (p38), Src and phosphatidylinositol 3-kinase (PI3K) pathways, have been reported to mediate TGF-β effects in a context-dependent manner [32][27]. TGF-β, via Smad2/3, also induces Foxp3 (a master regulator of Tregs) in naïve T cells and inhibits the proliferation of immune cells as well as cytokine production via Foxp3-dependent and -independent mechanisms [22,33][17][28]. Foxp3 inhibits secretion of proinflammatory cytokines, (including interleukin (IL)-2, IFN-γ, IL-4 and IL-17), enhances expression of anti-inflammatory cytokines (such as IL-10 and TGF-β) and up-regulates cytotoxic T lymphocyte-associated protein (CTLA)4 [34][29]. TGF-β also induces Foxp3+ expression in invariant natural killer T (iNKT) cells and allows them to acquire an immunoregulatory phenotype similarly to Tregs [35][30]. Tregs are a major source of TGF-β, and TGF-β is one of the effector molecules of Tregs upon activation by Treg/dendritic cell (DC) interaction [32][27]. Tregs are proposed to be involved in immune tolerance not just by secreting soluble TGF-β and IL-10 but also through a membrane-bound TGF-β-mediated cell–cell contact mechanism [36][31]. TGF-β also plays an important role in generating induced Tregs (iTregs) from naive T cells [32][27]. TGF-β has been implicated in the maintenance of Foxp3 in thymus-derived natural (n) Tregs [37][32]. Another function of TGF-β in T-cells is Th17 differentiation [38][33]. It has been suggested that the role of TGF-β in Th17 differentiation is the suppression of Th1 and Th2 differentiation (i.e., suppression of the production of IFN-γ and IL-4) since these cytokines strongly inhibit Th17 differentiation. Th17 cells produce IL-17 and IFN-γ, which support mucosal defense against bacteria, but tend to promote intestinal inflammation [38,39][33][34]. IL-17 production leads to expression of chemokines and other proinflammatory cytokines (such as IL-6 and TNFα) [40][35]. Overall, TGF-β through the inhibition of effector Th cell differentiation, induction of naive T cells into regulatory T cells, inhibition of the proliferation of T cells and B cells, inhibition of effector cytokine production (such as IL-2, IFN-γ and IL-4) and suppression of macrophages, DCs and natural killer (NK) cells regulates immune responses [32][27]. TGF-β contributed to the development of an ”inflammatory energy” macrophage phenotype, which is characterised by a lack of proinflammatory cytokine production under inflammatory stimuli but retention of phagocytic and bactericidal activity [18][13]. TGF-β production and signalling by T-cells are also important steps in the development of regulatory intraepithelial lymphocytes (IELs) in the intestinal epithelium [41][36]. TGF-β modulates the barrier function of the epithelium by regulating the expression levels of tight junction proteins and adhesion molecules [42][37]. Moreover, TGF-β is capable of degrading toll-like receptor (TLR)2 on epithelial cells [43][38]. TGF-β inhibits mast cell growth and downregulates the expression of membrane Ig-E receptors to attenuate the release of histamine, cysteinyl leukotrienes and TNF-α [35][30]. TGF-β also functions as a negative autocrine feedback regulator to prevent tissue injury caused by excessive nitric oxide (NO) [44,45][39][40]. Furthermore, it also regulates cell proliferation by controlling the expression of cell cycle regulators [46][41].

2.3. Role of Transforming Growth Factor-β in IBD

Stimulation of colonic epithelial cells with pathogenic bacteria and/or cytokine results in the up-regulation of a distinct array of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 that are key elements in the pathophysiology of IBD [47,48][42][43]. Once the inflammatory response has been initiated, efficient and prompt resolution of inflammation is important in order to minimise tissue injury and restore the integrity of the mucosal barrier [49][44]. The main function of TGF-β is expansion and survival of Treg cells that control the immune response and tolerance [50][45]. A reduction in Treg differentiation has been reported as a result of impaired TGF-β signalling in patients with IBD [51][46]. Tissue TGF-β levels are increased in the setting of IBD, but this may not be sufficient to counteract the ongoing inflammation [51][46]. This event is attributable to the remarkable upregulation of Smad7, blocking TGF-β-mediated IκBa transcription, in conjunction with the effects of TGF-β and IL-6, leading to the increased production of Th17 cells [52][47]. Pre-incubation of normal lamina propria mononuclear cells with TGF-β could prevent TNF-α-induced NF-κB activation [53][48]. This phenomenon results from an elevated pSmad3, which promotes IκBa transcription and reduces NF-κB entering into the nucleus, thus down-regulating inflammatory cytokine expression [54][49]. Biopsy specimens obtained from individuals with a normal (un-inflamed) colon that were exposed to anti-TGF-β antibodies exhibited downregulation of T-cell apoptosis and an increase in the production of proinflammatory cytokines including interferon-γ, TNF-α, IL-2, IL-6, IL-8 and IL-17 [55][50].

2.4. Therapeutic Approaches Related to TGF-β

Several therapeutic approaches involving TGF-β have been considered for the treatment of IBD. These involve direct administration of TGF-β and use of foods with enhanced or high content of TGF-β. However, preservation of the biological activity of TGF-β during the passage through the length of the GI tract has to be considered. Conway et al. [56][51] worked on the encapsulation of all-trans retinoic acid (ATRA) and TGF-β separately and then oral administration of loaded microspheres alone or in combination in a murine model of IBD. The authors reported that the activity of encapsulated TGF-β was fully preserved and had optimal therapeutic effects on gut inflammation through local induction of regulatory T-cells. In another study, Hammer et al. [57][52] investigated the oral administration of TreXTAM (a combination of encapsulated TGF-β along with ATRA) in rats. A reduction in local and systemic baseline levels of active TGF-β was observed. According to the known effects of TGF-β on fibrosis [7][53], this negative feedback suggests that encapsulated TGF-β may have a potential role in the prevention of IBD-associated fibrosis. A number of reports have evaluated the delivery of TGF-β within foods, in enteral formulae or directly via gavage in animal models with mucosal inflammation. Feeding with an enteral diet containing TGF-β2 resulted in improvement in body weight, lower pathological scores and lower Serum Amyloid A (SAA) levels in an IL-10 knockout mouse model of IBD [4]. Maheshvari et al. [58][54] reported that enteral supplementation of TGF-β2 protected mice from an experimental necrotising enterocolitis (NEC)-like injury by suppression of macrophage cytokine production and mucosal inflammatory responses in the developing intestine. In another animal study, gavaged TGF-β1 protected the immature gut from the development of NEC via suppression of immune effects on the intestinal epithelium along with a reduction in systemic IL-6 and IFN-γ levels [59][55]. Furthermore, diet enriched with TGF-β2 prevented mucosal injury, enhanced p-ERK and β-catenin induced enterocyte proliferation, inhibited enterocyte apoptosis and improved intestinal recovery in rats with experimentally methotrexate-induced intestinal mucositis [60][56]. Modulen IBD (Nestlé Health Science, Vevey, Switzerland) is a polymeric enteral formula rich in TGF-β that has been evaluated in a number of animal and clinical studies. In a rat model, for example, the administration of this formula provided protection against weight loss, hypoalbuminemia, acidosis, and GI mucosal damage [61][57]. Santactiv Digest powder (https://www.pharmacypanayiotou.com (accessed on 30 March 2023)) is another polymeric product featuring colostrum-derived TGF-β2 supplemented with probiotics (Bacillus coagulans) and n-3 fatty acids. Ferreira et al. [62][58] assessed the effects of nutritional supplementation with and without Modulen for 3 months in individuals with active CD. The patients receiving the TGF-β2-enriched formula showed an improvement in histologic parameters and reduced C-reactive protein (CRP) levels. Beaupel et al. [63][59] reported the preoperative administration of Modulen to be beneficial in high-risk patients with complicated CD, with reduced postoperative morbidity. In another study, 29 adults with active CD received Modulen IBD for 4 weeks [14][9]. Clinical improvement was noticed in 69% of the patients. In addition, nutritional parameters and inflammatory markers improved within the four weeks of the pilot study. Davanço et al. [64][60] observed that the intake of whey protein supplemented with TGF-β by patients with CD resulted in improved lean body mass, while concurrently reducing the fat percentage. Triantafillidis et al. [65][61] compared the results of the administration of Modulen IBD with those of mesalazine in a group of patients with CD for six months. At the end of the trial, no significant differences were observed in remission between two groups. They did report that high density lipoprotein (HDL) levels increased while low density lipoprotein (LDL) levels decreased in the patients receiving formula. This is relevant, as HDL can modulate LDL oxidation, LDL-induced cytokine production and inflammation [66][62]. In another study, Triantafillidis et al. [67][63] reported complete remission of scleritis and psoriasis in a patient with CD after treatment with Modulen IBD for five weeks. Two different polymeric formulae rich in TGF-β were used in two studies for 8 weeks as exclusive diets [68,69][64][65]. The first of these was a small study of patients with CD mainly affecting the small bowel while the second one included patients with different disease locations. The TGF-β formulae were effective in inducing remission and mucosal healing. Biochemical markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C reactive protein (CRP), normalised while serum levels of albumin increased with treatment. Colonic histological scores also improved significantly. It is of interest that there was a reduction in the mRNA levels for IL-1, IL-8 and IFN-γ; however, endogenous TGF-β increased.

3. Activins

3.1. General Aspects of Activins

Activins, which are also members of the TGF-β superfamily, have been shown to regulate a number of different cellular functions, including cell proliferation, differentiation and apoptosis [81,82][66][67]. Activins are expressed in almost every cell type, including epithelial cells, macrophages and fibroblasts [83,84][68][69]. Several different forms of activin are recognised: activin A is a homodimer of two activin A subunits, activin B is a homodimer of two activin B subunits; and activin AB is a heterodimer of these two subunits. Activin C, D, and E subunits also occur in mammals [85,86][70][71].

3.2. Biological Activity of Activins

Activins bind to one of two specific type 2 activin receptors (ACVR2A or ACVR2B) on the cell surface, which dimerise with a type 1 activin receptor serine/threonine kinase (activin receptor-like kinase, ALK) [87,88][72][73]. This leads to phosphorylation of the intracellular Smad proteins 2 and 3, which then form a heteromeric transcription factor with Smad4 [89][74] and translocate to the nucleus [90][75]. The downstream effects of Smad2/3 signalling depend on the cell type and cofactors associated with the Smad2/3-4 complex. This is the same transcription factor cascade activated by TGF-β. Furthermore, activins promote additional signalling pathways via TRAF6 and downstream activation of the MAP kinases, p38 MAPK, JNK and ERK1/2 [91,92,93][76][77][78]. The activity of activin is modulated by the synthesis and expression of activin receptors and levels of inhibin, an antagonist, and follistatin, a neutralising binding protein that binds activins with high affinity and blocks their function [85,86][70][71].

3.3. Inflammatory and Physiological Roles of Activins

Activins regulate the activity of many cell types involved in inflammation, immunity and fibrosis through regulation of fundamental cellular functions such as proliferation, differentiation and apoptosis in diverse cell systems including epithelial cells [94,95][79][80]. In animal experiments, an early rise in systemic activin A levels after lipopolysaccharide (LPS) injection was illustrated [95,96][80][81]. Activin A has the potential to antagonise the local actions of IL-6 and IL-1 [97][82]. Failure of activin A to modulate the actions of these cytokines is linked to the persistently elevated levels of acute phase proteins seen in chronic disease states such as secondary amyloidosis [98][83]. Activin A is released early in the cascade of circulatory cytokines in systemic inflammatory processes, roughly coinciding with TNF-α and before IL-6 and follistatin are elicited [8][84]. Interestingly, monocyte secretion of activin A is enhanced upon contract with antigen-specific T cells [99][85] and following antigen sensitisation in the lung [100][86]. Activin A, via stimulation of quiescent macrophages, promotes the production of proinflammatory cytokines [101,102][87][88] and also promotes pro-inflammatory Th2-, Th9- and Tfh-related responses [103,104,105][89][90][91]. Activin A promotes inflammation by stimulating production of inflammatory mediators including TNF-α, IL-6 and IL-1β, and nitric oxide, whereas follistatin reduces oxidative stress and modulates the inflammatory process in tissue repair by neutralising activin A [105,106,107][91][92][93]. Following burns and in wound healing, activin A stimulates inflammation and production of pro-fibrogenic proteins such as endothelin and TNFα [108,109][94][95]. Clinical and animal studies have shown that activin A levels increase in both acute and chronic inflammation and correlate with the severity of illness [110,111,112][96][97][98]. Moreover, inhibition of activin function is shown to reduce inflammation, damage, fibrosis and morbidity/mortality in various disease models. In this regard, follistatin prevents fibrosis through inhibition of activin produced by cells in response to TGF-β [100,113][86][99].

3.4. Activins and T Helper 17 Cells

Th17 cells are known to exert both pathogenic and non-pathogenic functions. Pathogenic-Th17 cells express high amounts of pro-inflammatory molecules including GM-CSF and IL-23R, while non-pathogenic-Th17 cells express high amounts of IL-10 and CD5L that contribute to tissue homeostasis [114,115,116,117,118][100][101][102][103][104]. During autoimmune inflammation, Activin A drives pathogenic Th17 cell differentiation through an Activin-A-ALK4-ERK axis [119][105]. Thus, this axis could be considered as a therapeutic target for pathogenic-Th17-cell-related diseases including IBD, rheumatoid arthritis and asthma [112,120,121,122][98][106][107][108].

3.5. Roles of Activin in Inflammatory Bowel Disease

Activins appear to have various roles in the maintenance of intestinal homeostasis and in gut inflammation, with particular relevance to IBD [123][109]. Dignass et al. [124][110] showed the presence of activin receptors I and II throughout the GI tract of patients with IBD. Hubner and colleagues [125][111] demonstrated upregulation of activin A mRNA in the gut of individuals with IBD; in contrast, levels were undetectable in samples from healthy controls. Furthermore, activin A mRNA correlated positively with histological severity and IL-1 levels. Similarly, activin AB was also expressed only in the intestinal tissue from those with IBD. In contrast, activin B mRNA levels in most specimens from inflamed areas were only slightly higher than those in control tissue samples [124][110]. Animal studies have also demonstrated increased tissue and systemic levels of activin during experimental colitis [126][112].

3.6. Activin Signalling as an Emerging Target for Therapeutic Interventions

Activins are emerging as important diagnostic tools and therapeutic targets in inflammatory and fibrotic diseases. In particular, activin signalling contributes to the etiolopathogenesis of a variety of inflammatory diseases. Accordingly, activin inhibition may have clinical benefits in these settings [84][69]. There are a number of inhibitors of the activin receptor signalling pathways (IASPs), which have differing modes of action [127][113]. Firstly, ActRIIA or ActRIIB ectodomains fused with the Fc portion of human immunoglobulin (Ig)-G1 can act as soluble decoy receptors that trap ligand extracellularly [128,129][114][115]. Secondly, various antibodies, peptibodies or adnectins act to neutralise activin [130,131,132][116][117][118]. Thirdly, antibodies directed towards ActRIIA or ActRIIB (or both) prevent ligand–receptor interaction [133,134][119][120]. Finally, endogenous TGF-β superfamily antagonists, such as growth and differentiation factor (GDF)-associated serum protein [135][121] or follistatin (FST), can also interrupt activin receptor signalling [136,137][122][123]. Activin antagonists such as follistatin, an endogenous activin-binding protein, offer considerable promise as therapies in conditions as diverse as sepsis, liver fibrosis, acute lung injury, asthma, wound healing and ischaemia–reperfusion injury. IASPs have also been considered in muscle wasting conditions [137,138,139,140,141][123][124][125][126][127] and various inflammatory disorders [142,143,144][128][129][130]. Numerous IASPs have been developed and evaluated in different settings [145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156]. One such example is Bimagrumab, an anti-ActRIIA/IIB antibody, which appears to have a beneficial role in muscle disorders [156,157,158,159][142][143][144][145]. This agent appears to also affect sex hormone profile, likely secondary to the effect of activin upon the gonadotropin-releasing hormone [171,172][157][158]. Whilst these agents have not yet been evaluated in the setting of IBD, their underlying mechanisms of action and their distribution in the gut suggest potential roles in IBD.

4. Follistatin

4.1. General Aspects of Follistatin

Follistatin (FST), another member of the TGF-β superfamily, is a multifunctional regulatory protein secreted by many tissues [173][159]. FST has a characteristic multidomain structure. Different isoforms can be found, consequent of alternative splicing of the corresponding gene and post-translational modification [174,175][160][161]. FST288 comprises 288 amino acids and is a locally acting form of FST characterised by a high affinity for heparin, a key component of the extracellular matrix and cell surface glycoproteins [174,176,177][160][162][163]. In contrast, FST315 consists of 315 amino acids and has a significantly reduced affinity for heparin because of the presence of an additional acidic C-terminal domain [178,179][164][165]. It represents the major circulating FST isoform. Another isoform, FST303, is likely produced by proteolytic cleavage of FST315 [102][88]. FST binds to and neutralises TGF-β superfamily members including activins, growth differentiation factor 8 (GDF8, myostatin) and GDF11 with high affinity. Neutralisation is achieved extracellularly when two FST molecules surround and sequester the receptor-binding sites of these ligands [175,179,180][161][165][166]. Follistatin is expressed on the surface of the target cells. FS288 is more potent than FST 315 and binds to activin A with very high affinity (50 pM) and activin B with a 10-fold lower affinity [176,179,181][162][165][167]. Activins trapped irreversibly by FST 288 are endocytosed into the cell and inactivated by proteolysis [181][167].

4.2. The Role of Follistatin in Inflammation and Tissue Repair

Follistatin has regulatory roles in several inflammatory and immune processes. In sheep, after in vivo challenge with LPS, up-regulation of FST follows that of activins [95][80]. In mice, blocking the actions of activin A following exposure to LPS with FST alters the induced cytokine cascade, attenuating the rise of TNFα and altering the levels of other inflammatory cytokines (e.g., IL1β and IL-6) [182][168]. Furthermore, FST is shown to reduce oxidative stress and modulate the inflammatory process in tissue repair by neutralising activin A [106,107][92][93]. In general, the activin/follistatin system contributes to tissue regenerative processes [183,184][169][170]. Neutralisation of activin in rats by FST promoted regeneration of hepatocytes after partial hepatectomy [185,186][171][172] and tubular epithelial regeneration after renal ischaemia [187][173]. A single administration of FST into the portal vein was much more effective than several administrations of hepatocyte growth factor in promoting liver regeneration and DNA was synthesised several hours earlier than in control [188,189][174][175]. FST attenuated radiation-induced fibrosis in a murine model [109][95] and diminished bleomycin-induced pulmonary fibrosis in mice by attenuating the proinflammatory and profibrotic actions of activin A [113][99]. In this regard, FST prevented fibrosis through inhibition of the activin produced by cells in response to TGF-β [100,113][86][99]. However, activin inhibition through FST did not affect TGF-β-induced growth suppression, suggesting that activin inhibition may specifically inhibit pro-oncogenic TGF-β functions while preserving its growth suppressive functions [190][176].

4.3. The Role of Follistatin in Intestinal Inflammation

Follistatin also appears to have particular roles in inflammatory processes in the GI tract. Administration of FST resulted in improvements in three distinct murine models of colitis [127][113]. In one model of colitis induced by administration of the hapten trinitrobenzene sulfonic acid (TNBS), FST pretreatment improved survival and reduced pro-inflammatory proteins. Rescue treatment with FST also resulted in improved histological scores in this model. Further to this, these researchers also demonstrated that FST administration reduced the severity of colitis in mice exposed to dextran sulfate sodium (DSS) and in the IL-10 knockout murine model [127][113]. These findings were supported by the results of a second study. Zhang et al. [191][177] demonstrated similar beneficial effects of FST using the DSS model and mice with a mdr1a knockout. Follistatin also appeared to enhance epithelial cell growth with consequent tissue repair and reduced apoptotic rate in mice exposed to DSS, reversing the adverse effects of activins upon the epithelium. A recent study showed that FST also strongly reduces macrophage trafficking in the epidermis [192][178]. Given the role of macrophages in these murine models of gut inflammation, this may be an additional component of the anti-inflammatory outcomes seen with FST. FST-based protein therapeutics also comprise an emerging class of pharmaceuticals for the treatment of muscular diseases. The first FST-based drug in clinical development [138,161][124][147]; ACE-083, upon intramuscular injection, acts as ligand trap for different cytokines of the TGF-β superfamily and thus interferes with ActRIIA and ActRIIB activation [138,161][124][147]. FollistatinΔHBS-Fc, based on follistatin 315, has been evaluated as a systemic therapy for muscle injury and osteoporosis in preclinical disease models [126,193][112][179]. Whilst these agents have not yet been assessed in the setting of IBD, the in vitro data and the understanding of the underlying mechanisms of action suggest that they may also have applications for IBD.

References

  1. McQuaid, K.R. Inflammatory Bowel Disease. In Current Medical Diagnosis & Treatment; Papadakis, M.A., McPhee, S.J., Rabow, M.W., McQuaid, K.R., Eds.; McGraw-Hill Education: New York, NY, USA, 2022.
  2. Ledder, O.; Sonnino, M.; Birimberg-Schwartz, L.; Escher, J.C.; Russell, R.K.; Orlanski-Meyer, E.; Matar, M.; Assa, A.; Tzion, R.L.; Shteyer, E.; et al. Appraisal of the PIBD-classes Criteria: A Multicentre Validation. J. Crohn’s Colitis 2020, 14, 1672–1679.
  3. Ahluwalia, B.; Moraes, L.; Magnusson, M.K.; Öhman, L. Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies. Scand. J. Gastroenterol. 2018, 53, 379–389.
  4. Oz, H.S.; Ray, M.; Chen, T.S.; McClain, C.J. Efficacy of a transforming growth factor β2 containing nutritional support formula in a murine model of inflammatory bowel disease. J. Am. Coll. Nutr. 2004, 23, 220–226.
  5. Chang, H.; Brown, C.W.; Matzuk, M.M. Genetic analysis of the mammalian transforming growth factor-β superfamily. Endocr. Rev. 2002, 23, 787–823.
  6. Govinden, R.; Bhoola, K. Genealogy, expression, and cellular function of transforming growth factor-β. Pharmacol. Ther. 2003, 98, 257–265.
  7. Massagué, J.; Blain, S.W.; Lo, R.S. TGFβ signaling in growth control, cancer, and heritable disorders. Cell 2000, 103, 295–309.
  8. Letterio, J.J.; Roberts, A.B. Regulation of immune responses by TGF-beta. Annu. Rev. Immunol. 1998, 16, 137.
  9. Triantafillidis, J.K.; Stamataki, A.; Gikas, A.; Sklavaina, M.; Mylonaki, M.; Georgopoulos, F.; Mastragelis, A.; Cheracakis, P. Beneficial effect of a polymeric feed, rich in TGF-b, on adult patients with active Crohn’s disease: A pilot study. Ann. Gastroenterol. 2006, 19, 66–71.
  10. Zhang, Y.-Z.; Li, Y.-Y. Inflammatory bowel disease: Pathogenesis. World J. Gastroenterol. 2014, 20, 91.
  11. Li, M.O.; Wan, Y.Y.; Sanjabi, S.; Robertson, A.; Flavell, R.A. Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol. 2006, 24, 99.
  12. Kubiczkova, L.; Sedlarikova, L.; Hajek, R.; Sevcikova, S. TGF-β–an excellent servant but a bad master. J. Transl. Med. 2012, 10, 1–24.
  13. Smythies, L.E.; Sellers, M.; Clements, R.H.; Mosteller-Barnum, M.; Meng, G.; Benjamin, W.H.; Orenstein, J.M.; Smith, P.D. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J. Clin. Investig. 2005, 115, 66–75.
  14. Shen, Y.; Zhang, C.; Chen, Y. TGF-β in inflammatory bowel diseases: A tale of the Janus-like cytokine. Crit. Rev. Eukaryot. Gene Expr. 2015, 25, 335–347.
  15. Massagué, J. TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 2012, 13, 616–630.
  16. Huse, M.; Muir, T.W.; Xu, L.; Chen, Y.-G.; Kuriyan, J.; Massagué, J. The TGFβ receptor activation process: An inhibitor-to substrate-binding switch. Mol. Cell 2001, 8, 671–682.
  17. Li, M.O.; Flavell, R.A. TGF-β: A master of all T cell trades. Cell 2008, 134, 392–404.
  18. Klein, J.; Ju, W.; Heyer, J.; Wittek, B.; Haneke, T.; Knaus, P.; Kucherlapati, R.; Böttinger, E.P.; Nitschke, L.; Kneitz, B. B cell-specific deficiency for Smad2 in vivo leads to defects in TGF-β-directed IgA switching and changes in B cell fate. J. Immunol. 2006, 176, 2389–2396.
  19. Verstockt, B.; Ferrante, M.; Vermeire, S.; Van Assche, G. New treatment options for inflammatory bowel diseases. J. Gastroenterol. 2018, 53, 585–590.
  20. Monteleone, G.; Neurath, M.F.; Ardizzone, S.; Di Sabatino, A.; Fantini, M.C.; Castiglione, F.; Scribano, M.L.; Armuzzi, A.; Caprioli, F.; Sturniolo, G.C. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn’s disease. N. Engl. J. Med. 2015, 372, 1104–1113.
  21. Takimoto, T.; Wakabayashi, Y.; Sekiya, T.; Inoue, N.; Morita, R.; Ichiyama, K.; Takahashi, R.; Asakawa, M.; Muto, G.; Mori, T. Smad2 and Smad3 are redundantly essential for the TGF-β–mediated regulation of regulatory T plasticity and Th1 development. J. Immunol. 2010, 185, 842–855.
  22. McKarns, S.C.; Schwartz, R.H.; Kaminski, N.E. Smad3 is essential for TGF-β1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J. Immunol. 2004, 172, 4275–4284.
  23. Kim, B.-G.; Li, C.; Qiao, W.; Mamura, M.; Kasperczak, B.; Anver, M.; Wolfraim, L.; Hong, S.; Mushinski, E.; Potter, M. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 2006, 441, 1015–1019.
  24. Monteleone, G.; Kumberova, A.; Croft, N.M.; McKenzie, C.; Steer, H.W.; MacDonald, T.T. Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J. Clin. Investig. 2001, 108, 601–609.
  25. Monteleone, G.; Blanco, G.D.V.; Monteleone, I.; Fina, D.; Caruso, R.; Gioia, V.; Ballerini, S.; Federici, G.; Bernardini, S.; Pallone, F. Post-transcriptional regulation of Smad7 in the gut of patients with inflammatory bowel disease. Gastroenterology 2005, 129, 1420–1429.
  26. MacDonald, T.T.; DiSabatino, A.; Gordon, J.N. Immunopathogenesis of Crohn’s disease. J. Parenter. Enter. Nutr. 2005, 29, S118–S125.
  27. Yoshimura, A.; Wakabayashi, Y.; Mori, T. Cellular and molecular basis for the regulation of inflammation by TGF-β. J. Biochem. 2010, 147, 781–792.
  28. Chen, W.; Jin, W.; Hardegen, N.; Lei, K.; Li, L.; Marinos, N. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198, e86.
  29. Zhou, L.; Lopes, J.E.; Chong, M.M.; Ivanov, I.I.; Min, R.; Victora, G.D.; Shen, Y.; Du, J.; Rubtsov, Y.P.; Rudensky, A.Y. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 2008, 453, 236–240.
  30. Monteiro, M.; Almeida, C.F.; Caridade, M.; Ribot, J.C.; Duarte, J.; Agua-Doce, A.; Wollenberg, I.; Silva-Santos, B.; Graca, L. Identification of regulatory Foxp3+ invariant NKT cells induced by TGF-β. J. Immunol. 2010, 185, 2157–2163.
  31. Kullberg, M.C.; Hay, V.; Cheever, A.W.; Mamura, M.; Sher, A.; Letterio, J.J.; Shevach, E.M.; Piccirillo, C.A. TGF-β1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation. Eur. J. Immunol. 2005, 35, 2886–2895.
  32. Sakaguchi, S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 2004, 22, 531.
  33. Goto, Y.; Panea, C.; Nakato, G.; Cebula, A.; Lee, C.; Diez, M.G.; Laufer, T.M.; Ignatowicz, L.; Ivanov, I.I. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014, 40, 594–607.
  34. Ivanov, I.I.; Atarashi, K.; Manel, N.; Brodie, E.L.; Shima, T.; Karaoz, U.; Wei, D.; Goldfarb, K.C.; Santee, C.A.; Lynch, S.V. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009, 139, 485–498.
  35. Xavier, R.J.; Podolsky, D.K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007, 448, 427–434.
  36. Konkel, J.E.; Maruyama, T.; Carpenter, A.C.; Xiong, Y.; Zamarron, B.F.; Hall, B.E.; Kulkarni, A.B.; Zhang, P.; Bosselut, R.; Chen, W. Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nat. Immunol. 2011, 12, 312–319.
  37. Biancheri, P.; Di Sabatino, A.; Corazza, G.R.; MacDonald, T.T. Proteases and the gut barrier. Cell Tissue Res. 2013, 351, 269–280.
  38. Ruiz, P.A.; Shkoda, A.; Kim, S.C.; Sartor, R.B.; Haller, D. IL-10 gene-deficient mice lack TGF-beta/Smad-mediated TLR2 degradation and fail to inhibit proinflammatory gene expression in intestinal epithelial cells under conditions of chronic inflammation. Ann. N. Y. Acad. Sci. 2006, 1072, 389–394.
  39. Ding, A.; Nathan, C.; Graycar, J.; Derynck, R.; Stuehr, D.; Srimal, S. Macrophage deactivating factor and transforming growth factors-beta 1-beta 2 and-beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J. Immunol. 1990, 145, 940–944.
  40. Nelson, B.; Ralph, P.; Green, S.; Nacy, C. Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1. J. Immunol. 1991, 146, 1849–1857.
  41. Polyak, K.; Kato, J.; Solomon, M.J.; Sherr, C.J.; Massague, J.; Roberts, J.M.; Koff, A. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev. 1994, 8, 9–22.
  42. Jung, H.C.; Eckmann, L.; Yang, S.; Panja, A.; Fierer, J.; Morzycka-Wroblewska, E.; Kagnoff, M. A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. J. Clin. Investig. 1995, 95, 55–65.
  43. Neurath, M.F. Cytokines in inflammatory bowel disease. Nat. Rev. Immunol. 2014, 14, 329–342.
  44. Mladenova, D.; Kohonen-Corish, M.R. Mouse models of inflammatory bowel disease-insights into the mechanisms of inflammation-associated colorectal cancer. In Vivo 2012, 26, 627–646.
  45. Li, M.O.; Flavell, R.A. Contextual regulation of inflammation: A duet by transforming growth factor-β and interleukin-10. Immunity 2008, 28, 468–476.
  46. Ihara, S.; Hirata, Y.; Koike, K. TGF-β in inflammatory bowel disease: A key regulator of immune cells, epithelium, and the intestinal microbiota. J. Gastroenterol. 2017, 52, 777–787.
  47. Feagins, L.A. Role of transforming growth factor-β in inflammatory bowel disease and colitis-associated colon cancer. Inflamm. Bowel Dis. 2010, 16, 1963–1968.
  48. Monteleone, G.; Mann, J.; Monteleone, I.; Vavassori, P.; Bremner, R.; Fantini, M.; Blanco, G.D.V.; Tersigni, R.; Alessandroni, L.; Mann, D. A failure of transforming growth factor-β1 negative regulation maintains sustained NF-κB activation in gut inflammation. J. Biol. Chem. 2004, 279, 3925–3932.
  49. Mangan, P.R.; Harrington, L.E.; O’Quinn, D.B.; Helms, W.S.; Bullard, D.C.; Elson, C.O.; Hatton, R.D.; Wahl, S.M.; Schoeb, T.R.; Weaver, C.T. Transforming growth factor-β induces development of the TH17 lineage. Nature 2006, 441, 231–234.
  50. Di Sabatino, A.; Pickard, K.M.; Rampton, D.; Kruidenier, L.; Rovedatti, L.; Leakey, N.A.; Corazza, G.R.; Monteleone, G.; MacDonald, T.T. Blockade of transforming growth factor β upregulates T-box transcription factor T-bet, and increases T helper cell type 1 cytokine and matrix metalloproteinase-3 production in the human gut mucosa. Gut 2008, 57, 605–612.
  51. Conway, T.F.; Hammer, L.; Furtado, S.; Mathiowitz, E.; Nicoletti, F.; Mangano, K.; Egilmez, N.K.; Auci, D.L. Oral delivery of particulate transforming growth factor beta 1 and all-trans retinoic acid reduces gut inflammation in murine models of inflammatory bowel disease. J. Crohn’s Colitis 2015, 9, 647–658.
  52. Hammer, L.; Furtado, S.; Mathiowitz, E.; Auci, D.L. Oral encapsulated transforming growth factor β1 reduces endogenous levels: Effect on inflammatory bowel disease. World J. Gastrointest. Pharmacol. Ther. 2020, 11, 79.
  53. de Kretser, D.M.; O’Hehir, R.E.; Hardy, C.L.; Hedger, M.P. The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair. Mol. Cell. Endocrinol. 2012, 359, 101–106.
  54. Maheshwari, A.; Kelly, D.R.; Nicola, T.; Ambalavanan, N.; Jain, S.K.; Murphy–Ullrich, J.; Athar, M.; Shimamura, M.; Bhandari, V.; Aprahamian, C. TGF-β2 suppresses macrophage cytokine production and mucosal inflammatory responses in the developing intestine. Gastroenterology 2011, 140, 242–253.
  55. Shiou, S.-R.; Yu, Y.; Guo, Y.; Westerhoff, M.; Lu, L.; Petrof, E.O.; Sun, J.; Claud, E.C. Oral administration of transforming growth factor-β1 (TGF-β1) protects the immature gut from injury via Smad protein-dependent suppression of epithelial nuclear factor κB (NF-κB) signaling and proinflammatory cytokine production. J. Biol. Chem. 2013, 288, 34757–34766.
  56. Ben-Lulu, S.; Pollak, Y.; Mogilner, J.; Bejar, J.; Coran, A.G.; Sukhotnik, I. Dietary transforming growth factor-beta 2 (TGF-β2) supplementation reduces methotrexate-induced intestinal mucosal injury in a rat. PLoS ONE 2012, 7, e45221.
  57. Harsha, W.T.; Kalandarova, E.; McNutt, P.; Irwin, R.; Noel, J. Nutritional supplementation with transforming growth factor-β, glutamine, and short chain fatty acids minimizes methotrexate-induced injury. J. Pediatr. Gastroenterol. Nutr. 2006, 42, 53–58.
  58. Ferreira, T.M.R.; Albuquerque, A.; Cancela Penna, F.G.; Macedo Rosa, R.; Correia, M.I.T.D.; Barbosa, A.J.A.; Salles Cunha, A.; Ferrari, M.d.L.A. Effect of Oral nutrition supplements and TGF-β2 on nutrition and inflammatory patterns in patients with active Crohn’s disease. Nutr. Clin. Pract. 2020, 35, 885–893.
  59. Beaupel, N.; Brouquet, A.; Abdalla, S.; Carbonnel, F.; Penna, C.; Benoist, S. Preoperative oral polymeric diet enriched with transforming growth factor-beta 2 (Modulen) could decrease postoperative morbidity after surgery for complicated ileocolonic Crohn’s disease. Scand. J. Gastroenterol. 2017, 52, 5–10.
  60. Davanço, T.; Leal, R.F.; Oya, V.; Lomazi, E.; dos Santos Vilela, M.M.; Coy, S.R.; Sgarbieri, V.; Ayrizono, M.d.L.S. Nutritional supplementation assessment with whey proteins and TGF-β in patients with Crohn’s disease. Nutr. Hosp. 2012, 27, 1286–1292.
  61. Triantafillidis, J.; Stamataki, A.; Gikas, A.; Malgarinos, G. Maintenance treatment of Crohn’s disease with a polymeric feed rich in TGF-β. Ann. Gastroenterol. 2010, 23, 113–118.
  62. Tabet, F.; Rye, K.-A. High-density lipoproteins, inflammation and oxidative stress. Clin. Sci. 2009, 116, 87–98.
  63. Triantafillidis, J.K.; Mantzaris, G.; Stamataki, A.; Asvestis, K.; Malgarinos, G.; Gikas, A. Complete remission of severe scleritis and psoriasis in a patient with active Crohn’s disease using Modulen IBD as an exclusive immunomodulating diet. J. Clin. Gastroenterol. 2008, 42, 550–551.
  64. Fell, J.; Paintin, M.; Arnaud-Battandier, F.; Beattie, R.; Hollis, A.; Kitching, P.; Donnet-Hughes, A.; MacDonald, T.; Walker-Smith, J. Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn’s disease. Aliment. Pharmacol. Ther. 2000, 14, 281–290.
  65. Beattie, R.; Schiffrin, E.; Donnet-Hughes, A.; Huggett, A.; Domizio, P.; MacDonald, T.; Walker-Smith, J. Polymeric nutrition as the primary therapy in children with small bowel Crohn’s disease. Aliment. Pharmacol. Ther. 1994, 8, 609–615.
  66. Kingsley, D. The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994, 8, 133–146.
  67. Massague, J. The transforming growth factor-beta family. Annu. Rev. Cell Biol. 1990, 6, 597–641.
  68. Chen, Y.-G.; Lui, H.M.; Lin, S.-L.; Lee, J.M.; Ying, S.-Y. Regulation of cell proliferation, apoptosis, and carcinogenesis by activin. Exp. Biol. Med. 2002, 227, 75–87.
  69. Tsuchida, K.; Nakatani, M.; Hitachi, K.; Uezumi, A.; Sunada, Y.; Ageta, H.; Inokuchi, K. Activin signaling as an emerging target for therapeutic interventions. Cell Commun. Signal. 2009, 7, 15.
  70. Mather, J.P.; Moore, A.; Li, R.-H. Activins, inhibins, and follistatins: Further thoughts on a growing family of regulators. Proc. Soc. Exp. Biol. Med. 1997, 215, 209–222.
  71. Ying, S.-Y.; Zhang, Z.; Furst, B.; Batres, Y.; Huang, G.; Li, G. Activins and activin receptors in cell growth. Proc. Soc. Exp. Biol. Med. 1997, 214, 114–122.
  72. Herbertz, S.; Sawyer, J.S.; Stauber, A.J.; Gueorguieva, I.; Driscoll, K.E.; Estrem, S.T.; Cleverly, A.L.; Desaiah, D.; Guba, S.C.; Benhadji, K.A. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des. Devel. Ther. 2015, 9, 4479.
  73. Anderton, M.J.; Mellor, H.R.; Bell, A.; Sadler, C.; Pass, M.; Powell, S.; Steele, S.J.; Roberts, R.R.; Heier, A. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol. Pathol. 2011, 39, 916–924.
  74. Pearsall, R.S.; Canalis, E.; Cornwall-Brady, M.; Underwood, K.W.; Haigis, B.; Ucran, J.; Kumar, R.; Pobre, E.; Grinberg, A.; Werner, E.D. A soluble activin type IIA receptor induces bone formation and improves skeletal integrity. Proc. Natl. Acad. Sci. USA 2008, 105, 7082–7087.
  75. Massagué, J.; Seoane, J.; Wotton, D. Smad transcription factors. Genes Dev. 2005, 19, 2783–2810.
  76. De Caestecker, M. The transforming growth factor-β superfamily of receptors. Cytokine Growth Factor Rev. 2004, 15, 1–11.
  77. Heldin, C.-H.; Landström, M.; Moustakas, A. Mechanism of TGF-β signaling to growth arrest, apoptosis, and epithelial–mesenchymal transition. Curr. Opin. Cell Biol. 2009, 21, 166–176.
  78. Zhang, L.; Deng, M.; Parthasarathy, R.; Wang, L.; Mongan, M.; Molkentin, J.D.; Zheng, Y.; Xia, Y. MEKK1 transduces activin signals in keratinocytes to induce actin stress fiber formation and migration. Mol. Cell. Biol. 2005, 25, 60–65.
  79. Chen, N.; Laadem, A.; Wilson, D.M.; Zhang, X.; Sherman, M.L.; Ritland, S.; Attie, K.M. Pharmacokinetics and exposure-response of luspatercept in patients with beta-thalassemia: Preliminary results from phase 2 studies. Blood 2016, 128, 2463.
  80. Jones, K.L.; Brauman, J.N.; Groome, N.P.; de Kretser, D.M.; Phillips, D.J. Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin. J. Endocrinol. 2000, 141, 1905–1908.
  81. Wu, H.; Chen, Y.; Winnall, W.R.; Phillips, D.J.; Hedger, M.P. Acute regulation of activin A and its binding protein, follistatin, in serum and tissues following lipopolysaccharide treatment of adult male mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2012, 303, R665–R675.
  82. Yu, E.; Dolter, K.; Shao, L.; Yu, J. Suppression of IL-6 biological activities by activin A and implications for inflammatory arthropathies. J. Clin. Exp. Immunol. 1998, 112, 126–132.
  83. Steel, D.M.; Whitehead, A.S. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol. Today 1994, 15, 81–88.
  84. Phillips, D.J.; Jones, K.L.; Scheerlinck, J.Y.; Hedger, M.P.; de Kretser, D.M. Evidence for activin A and follistatin involvement in the systemic inflammatory response. Mol. Cell. Endocrinol. 2001, 180, 155–162.
  85. Abe, M.; Shintani, Y.; Eto, Y.; Harada, K.; Kosaka, M.; Matsumoto, T. Potent induction of activin A secretion from monocytes and bone marrow stromal fibroblasts by cognate interaction with activated T cells. J. Leukoc. Biol. 2002, 72, 347–352.
  86. Karagiannidis, C.; Hense, G.; Martin, C.; Epstein, M.; Rückert, B.; Mantel, P.-Y.; Menz, G.; Uhlig, S.; Blaser, K.; Schmidt-Weber, C.B. Activin A is an acute allergen-responsive cytokine and provides a link to TGF-β–mediated airway remodeling in asthma. J. Allergy Clin. Immunol. 2006, 117, 111–118.
  87. Iemura, S.-i.; Yamamoto, T.S.; Takagi, C.; Uchiyama, H.; Natsume, T.; Shimasaki, S.; Sugino, H.; Ueno, N. Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc. Natl. Acad. Sci. USA 1998, 95, 9337–9342.
  88. Sugino, K.; Kurosawa, N.; Nakamura, T.; Takio, K.; Shimasaki, S.; Ling, N.; Titani, K.; Sugino, H. Molecular heterogeneity of follistatin, an activin-binding protein. Higher affinity of the carboxyl-terminal truncated forms for heparan sulfate proteoglycans on the ovarian granulosa cell. J. Biol. Chem. 1993, 268, 15579–15587.
  89. Jones, C.P.; Gregory, L.G.; Causton, B.; Campbell, G.A.; Lloyd, C.M. Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology. J. Allergy Clin. Immunol. 2012, 129, 1000–1010.
  90. Locci, M.; Wu, J.E.; Arumemi, F.; Mikulski, Z.; Dahlberg, C.; Miller, A.T.; Crotty, S. Activin A programs the differentiation of human TFH cells. Nat. Immunol. 2016, 17, 976–984.
  91. Ogawa, K.; Funaba, M.; Chen, Y.; Tsujimoto, M. Activin A functions as a Th2 cytokine in the promotion of the alternative activation of macrophages. J. Immunol. 2006, 177, 6787–6794.
  92. Harrison, C.A.; Gray, P.C.; Vale, W.W.; Robertson, D.M. Antagonists of activin signaling: Mechanisms and potential biological applications. Trends Endocrinol. Metab. 2005, 16, 73–78.
  93. Westall, G.P.; Snell, G.I.; Loskot, M.; Levvey, B.; O’Hehir, R.; Hedger, M.P.; de Kretser, D.M. Activin biology after lung transplantation. Transpl. Direct 2017, 3, e159.
  94. Hedger, M.P.; Winnall, W.R.; Phillips, D.J.; de Kretser, D.M. The regulation and functions of activin and follistatin in inflammation and immunity. Vitam. Horm. 2011, 85, 255–297.
  95. Forrester, H.B.; De Kretser, D.M.; Leong, T.; Hagekyriakou, J.; Sprung, C.N. Follistatin attenuates radiation-induced fibrosis in a murine model. PLoS ONE 2017, 12, e0173788.
  96. Yndestad, A.; Larsen, K.-O.; Øie, E.; Ueland, T.; Smith, C.; Halvorsen, B.; Sjaastad, I.; Skjønsberg, O.H.; Pedersen, T.M.; Anfinsen, O.-G. Elevated levels of activin A in clinical and experimental pulmonary hypertension. J. Appl. Physiol. 2009, 106, 1356–1364.
  97. Phillips, D.J.; de Kretser, D.M.; Hedger, M.P. Activin and related proteins in inflammation: Not just interested bystanders. Cytokine Growth Factor Rev. 2009, 20, 153–164.
  98. Michel, U.; Ebert, S.; Phillips, D.; Nau, R. Serum concentrations of activin and follistatin are elevated and run in parallel in patients with septicemia. Eur. J. Endocrinol. 2003, 148, 559–564.
  99. Aoki, F.; Kurabayashi, M.; Hasegawa, Y.; Kojima, I. Attenuation of bleomycin-induced pulmonary fibrosis by follistatin. Am. J. Respir. Crit. Care Med. 2005, 172, 713–720.
  100. Gaublomme, J.T.; Yosef, N.; Lee, Y.; Gertner, R.S.; Yang, L.V.; Wu, C.; Pandolfi, P.P.; Mak, T.; Satija, R.; Shalek, A.K. Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 2015, 163, 1400–1412.
  101. Lee, Y.; Awasthi, A.; Yosef, N.; Quintana, F.J.; Xiao, S.; Peters, A.; Wu, C.; Kleinewietfeld, M.; Kunder, S.; Hafler, D.A. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 2012, 13, 991–999.
  102. McGeachy, M.J.; Bak-Jensen, K.S.; Chen, Y.; Tato, C.M.; Blumenschein, W.; McClanahan, T.; Cua, D.J. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell–mediated pathology. Nat. Immunol. 2007, 8, 1390–1397.
  103. Omenetti, S.; Bussi, C.; Metidji, A.; Iseppon, A.; Lee, S.; Tolaini, M.; Li, Y.; Kelly, G.; Chakravarty, P.; Shoaie, S. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity 2019, 51, 77–89.
  104. Wang, C.; Yosef, N.; Gaublomme, J.; Wu, C.; Lee, Y.; Clish, C.B.; Kaminski, J.; Xiao, S.; Zu Horste, G.M.; Pawlak, M. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 2015, 163, 1413–1427.
  105. Wu, B.; Zhang, S.; Guo, Z.; Bi, Y.; Zhou, M.; Li, P.; Seyedsadr, M.; Xu, X.; Li, J.-l.; Markovic-Plese, S. The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation. Immunity 2021, 54, 308–323.
  106. Korn, T.; Bettelli, E.; Oukka, M.; Kuchroo, V.K. IL-17 and Th17 Cells. Annu. Rev. Immunol. 2009, 27, 485–517.
  107. Sideras, P.; Apostolou, E.; Stavropoulos, A.; Sountoulidis, A.; Gavriil, A.; Apostolidou, A.; Andreakos, E. Activin, neutrophils, and inflammation: Just coincidence? Semin. Immunopathol. 2013, 35, 481–499.
  108. Werner, S.; Alzheimer, C. Roles of activin in tissue repair, fibrosis, and inflammatory disease. Cytokine Growth Factor Rev. 2006, 17, 157–171.
  109. Sonoyama, K.; Rutatip, S.; Kasai, T. Gene expression of activin, activin receptors, and follistatin in intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 2000, 278, G89–G97.
  110. Dignass, A.; Jung, S.; Harder-d’Heureuse, J.; Wiedenmann, B. Functional relevance of activin A in the intestinal epithelium. Scand. J. Gastroenterol. 2002, 37, 936–943.
  111. Hübner, G.; Brauchle, M.; Gregor, M.; Werner, S. Activin A: A novel player and inflammatory marker in inflammatory bowel disease? Lab. Investig. 1997, 77, 311–318.
  112. Lodberg, A. Principles of the activin receptor signaling pathway and its inhibition. Cytokine Growth Factor Rev. 2021, 60, 1–17.
  113. Dohi, T.; Ejima, C.; Kato, R.; Kawamura, Y.I.; Kawashima, R.; Mizutani, N.; Tabuchi, Y.; Kojima, I. Therapeutic potential of follistatin for colonic inflammation in mice. Gastroenterology 2005, 128, 411–423.
  114. Souza, T.A.; Chen, X.; Guo, Y.; Sava, P.; Zhang, J.; Hill, J.J.; Yaworsky, P.J.; Qiu, Y. Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators. Mol. Endocrinol. 2008, 22, 2689–2702.
  115. McPherron, A.C.; Huynh, T.V.; Lee, S.-J. Redundancy of myostatin and growth/differentiation factor 11 function. BMC Dev. Biol. 2009, 9, 24.
  116. Sinha, M.; Jang, Y.C.; Oh, J.; Khong, D.; Wu, E.Y.; Manohar, R.; Miller, C.; Regalado, S.G.; Loffredo, F.S.; Pancoast, J.R. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014, 344, 649–652.
  117. Egerman, M.A.; Cadena, S.M.; Gilbert, J.A.; Meyer, A.; Nelson, H.N.; Swalley, S.E.; Mallozzi, C.; Jacobi, C.; Jennings, L.L.; Clay, I. GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 2015, 22, 164–174.
  118. Hinken, A.C.; Powers, J.M.; Luo, G.; Holt, J.A.; Billin, A.N.; Russell, A.J. Lack of evidence for GDF 11 as a rejuvenator of aged skeletal muscle satellite cells. Aging Cell 2016, 15, 582–584.
  119. Latres, E.; Pangilinan, J.; Miloscio, L.; Bauerlein, R.; Na, E.; Potocky, T.B.; Huang, Y.; Eckersdorff, M.; Rafique, A.; Mastaitis, J. Myostatin blockade with a fully human monoclonal antibody induces muscle hypertrophy and reverses muscle atrophy in young and aged mice. Skelet. Muscle 2015, 5, 34.
  120. Becker, C.; Lord, S.R.; Studenski, S.A.; Warden, S.J.; Fielding, R.A.; Recknor, C.P.; Hochberg, M.C.; Ferrari, S.L.; Blain, H.; Binder, E.F. Myostatin antibody (LY2495655) in older weak fallers: A proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2015, 3, 948–957.
  121. Bogdanovich, S.; Perkins, K.J.; Krag, T.O.; Whittemore, L.-A.; Khurana, T.S. Myostatin propeptide-mediated amelioration of dystrophic pathophysiology. FASEB J. 2005, 19, 543–549.
  122. Goncalves, M.D.; Pistilli, E.E.; Balduzzi, A.; Birnbaum, M.J.; Lachey, J.; Khurana, T.S.; Ahima, R.S. Akt deficiency attenuates muscle size and function but not the response to ActRIIB inhibition. PLoS ONE 2010, 5, e12707.
  123. Zhou, X.; Wang, J.L.; Lu, J.; Song, Y.; Kwak, K.S.; Jiao, Q.; Rosenfeld, R.; Chen, Q.; Boone, T.; Simonet, W.S. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 2010, 142, 531–543.
  124. Pearsall, R.; Davies, M.; Cannell, M.; Li, J.; Widrick, J.; Mulivor, A.; Wallner, S.; Troy, M.; Spaits, M.; Liharska, K. Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease. Sci. Rep. 2019, 9, 11392.
  125. Pistilli, E.E.; Bogdanovich, S.; Goncalves, M.D.; Ahima, R.S.; Lachey, J.; Seehra, J.; Khurana, T. Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy. Am. J. Pathol. 2011, 178, 1287–1297.
  126. Sepulveda, P.V.; Lamon, S.; Hagg, A.; Thomson, R.E.; Winbanks, C.E.; Qian, H.; Bruce, C.R.; Russell, A.P.; Gregorevic, P. Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy. Sci. Rep. 2015, 5, 17535.
  127. Meier, D.; Lodberg, A.; Gvozdenovic, A.; Pellegrini, G.; Neklyudova, O.; Born, W.; Fuchs, B.; Eijken, M.; Botter, S.M. Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma. Cancer Med. 2021, 10, 286–296.
  128. Dankbar, B.; Fennen, M.; Brunert, D.; Hayer, S.; Frank, S.; Wehmeyer, C.; Beckmann, D.; Paruzel, P.; Bertrand, J.; Redlich, K. Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat. Med. 2015, 21, 1085–1090.
  129. Zhang, L.; Rajan, V.; Lin, E.; Hu, Z.; Han, H.; Zhou, X.; Song, Y.; Min, H.; Wang, X.; Du, J. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J. 2011, 25, 1653–1663.
  130. Zeng, R.; Glaubitz, S.; Schmidt, J. Antibody therapies in autoimmune inflammatory myopathies: Promising treatment options. Neurotherapeutics 2022, 19, 911–921.
  131. Joshi, S.R.; Liu, J.; Bloom, T.; Karaca Atabay, E.; Kuo, T.-H.; Lee, M.; Belcheva, E.; Spaits, M.; Grenha, R.; Maguire, M.C. Sotatercept analog suppresses inflammation to reverse experimental pulmonary arterial hypertension. Sci. Rep. 2022, 12, 1–18.
  132. Joshi, S.; Liu, J.; Pearsall, R.; Andre, P.; Li, G.; Kumar, R. Activin receptor type IIA-Fc (Sotatercept) suppresses inflammation to alleviate pulmonary arterial hypertension in preclinical models. Am. J. Respir. Crit. Care Med. 2020, 201, A3835.
  133. Raje, N.; Vallet, S. Sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein for the treatment of anemia and bone loss. Curr. Opin. Mol. Ther. 2010, 12, 586–597.
  134. Abdulkadyrov, K.M.; Salogub, G.N.; Khuazheva, N.K.; Sherman, M.L.; Laadem, A.; Barger, R.; Knight, R.; Srinivasan, S.; Terpos, E. Sotatercept in patients with osteolytic lesions of multiple myeloma. Br. J. Haematol. 2014, 165, 814–823.
  135. Sherman, M.L.; Borgstein, N.G.; Mook, L.; Wilson, D.; Yang, Y.; Chen, N.; Kumar, R.; Kim, K.; Laadem, A. Multiple-dose, safety, pharmacokinetic, and pharmacodynamic study of sotatercept (ActRIIA-IgG1), a novel erythropoietic agent, in healthy postmenopausal women. J. Clin. Pharmacol. 2013, 53, 1121–1130.
  136. Raftopoulos, H.; Laadem, A.; Hesketh, P.J.; Goldschmidt, J.; Gabrail, N.; Osborne, C.; Ali, M.; Sherman, M.L.; Wang, D.; Glaspy, J.A. Sotatercept (ACE-011) for the treatment of chemotherapy-induced anemia in patients with metastatic breast cancer or advanced or metastatic solid tumors treated with platinum-based chemotherapeutic regimens: Results from two phase 2 studies. Support. Care Cancer 2016, 24, 1517–1525.
  137. Humbert, M.; McLaughlin, V.; Gibbs, J.S.R.; Gomberg-Maitland, M.; Hoeper, M.M.; Preston, I.R.; Souza, R.; Waxman, A.B.; Ghofrani, H.-A.; Subias, P.E. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur. Respir. J. 2023, 61, 2201347.
  138. Bose, P.; Pemmaraju, N.; Masarova, L.; Bledsoe, S.D.; Daver, N.; Jabbour, E.; Kadia, T.M.; Estrov, Z.E.; Kornblau, S.M.; Andreeff, M. Sotatercept (ACE-011) for anemia of myelofibrosis: A phase 2 study. Blood 2020, 136, 10–11.
  139. Fenaux, P.; Kiladjian, J.J.; Platzbecker, U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood 2019, 133, 790–794.
  140. Jelkmann, W. Activin receptor ligand traps in chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 2018, 27, 351–357.
  141. Fenaux, P.; Platzbecker, U.; Mufti, G.J.; Garcia-Manero, G.; Buckstein, R.; Santini, V.; Díez-Campelo, M.; Finelli, C.; Cazzola, M.; Ilhan, O. Luspatercept in patients with lower-risk myelodysplastic syndromes. N. Engl. J. Med. 2020, 382, 140–151.
  142. Amato, A.A.; Sivakumar, K.; Goyal, N.; David, W.S.; Salajegheh, M.; Praestgaard, J.; Lach-Trifilieff, E.; Trendelenburg, A.-U.; Laurent, D.; Glass, D.J. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology 2014, 83, 2239–2246.
  143. Hanna, M.G.; Badrising, U.A.; Benveniste, O.; Lloyd, T.E.; Needham, M.; Chinoy, H.; Aoki, M.; Machado, P.M.; Liang, C.; Reardon, K.A. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): A randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2019, 18, 834–844.
  144. Rooks, D.S.; Laurent, D.; Praestgaard, J.; Rasmussen, S.; Bartlett, M.; Tankó, L.B. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J. Cachexia Sarcopenia Muscle 2017, 8, 727–734.
  145. Sivakumar, K.; Cochrane, T.I.; Sloth, B.; Ashar, H.; Laurent, D.; Tankó, L.B.; Amato, A.A. Long-term safety and tolerability of bimagrumab (BYM338) in sporadic inclusion body myositis. Neurology 2020, 95, e1971–e1978.
  146. Jagtap, K.; Hoff, L.S.; Conticini, E.; Naveen, R.; Gupta, L. Inflammaging in muscle the missing link between sarcopenia and idiopathic inflammatory myopathies. J. Anti. Aging Med. 2022, 1, 63–72.
  147. Glasser, C.E.; Gartner, M.R.; Wilson, D.; Miller, B.; Sherman, M.L.; Attie, K.M. Locally acting ACE-083 increases muscle volume in healthy volunteers. Muscle Nerve 2018, 57, 921–926.
  148. Statland, J.M.; Campbell, C.; Desai, U.; Karam, C.; Díaz-Manera, J.; Guptill, J.T.; Korngut, L.; Genge, A.; Tawil, R.N.; Elman, L. Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy. Muscle Nerve 2022, 66, 50–62.
  149. Shy, M.; Herrmann, D.; Thomas, F.; Quinn, C.; Statland, J.; Walk, D.; Johnson, N.; Subramony, S.; Karam, C.; Mozaffar, T. CMT and neurogenic disease: P. 339Preliminary phase 2 results for ACE-083, local muscle therapeutic, in patients with CMT1 and CMTX. Neuromuscul. Disord. 2018, 28, S132–S133.
  150. Thomas, F.P.; Brannagan, T.H.; Butterfield, R.J.; Desai, U.; Habib, A.A.; Herrmann, D.N.; Eichinger, K.J.; Johnson, N.E.; Karam, C.; Pestronk, A. Randomized phase 2 study of ACE-083 in patients with charcot-marie-tooth disease. Neurology 2022, 98, e2356–e2367.
  151. Statland, J.; Bravver, E.; Karam, C.; Elman, L.; Johnson, N.; Joyce, N. Results for a dose-escalation phase 2 study to evaluate ACE-083, a local muscle therapeutic, in patients with facioscapulohumeral muscular dystrophy. Neuromuscul. Disord. 2018, 28, S140.
  152. Thomas, F.P.; Shy, M.; Quinn, C.; Desai, U.; Herrmann, D.; Statland, J.; Subramony, S.; Brannagan, T.; Habib, A.A.; Karam, C. Results of a phase 2 double-blind placebo-controlled study of a local muscle therapeutic, ACE-083, in subjects with charcot-marie-tooth (CMT) disease (1514). Neurology 2020, 14, 1514.
  153. Statland, J.; Amato, A.; Bravver, E.; Campbell, C.; Elman, L.; Johnson, N.; Joyce, N.; Karam, C.; Kissel, J.; Korngut, L. Preliminary results from a phase 2 study to evaluate ACE-083, a local muscle therapeutic, in patients with facioscapulohumeral muscular dystrophy (S38. 001). Neurology 2018, 90, S38.001.
  154. Ghasemi, M.; Emerson Jr, C.P.; Hayward, L.J. Outcome measures in facioscapulohumeral muscular dystrophy clinical trials. Cells 2022, 11, 687.
  155. Lodberg, A.; van der Eerden, B.C.; Boers-Sijmons, B.; Thomsen, J.S.; Brüel, A.; van Leeuwen, J.P.; Eijken, M. A follistatin-based molecule increases muscle and bone mass without affecting the red blood cell count in mice. FASEB J. 2019, 33, 6001–6010.
  156. Latres, E.; Mastaitis, J.; Fury, W.; Miloscio, L.; Trejos, J.; Pangilinan, J.; Okamoto, H.; Cavino, K.; Na, E.; Papatheodorou, A. Activin A more prominently regulates muscle mass in primates than does GDF8. Nat. Commun. 2017, 8, 151153.
  157. Gregory, S.J.; Kaiser, U.B. Regulation of gonadotropins by inhibin and activin. Semin. Reprod. Med. 2004, 22, 253–267.
  158. Garito, T.; Zakaria, M.; Papanicolaou, D.A.; Li, Y.; Pinot, P.; Petricoul, O.; Laurent, D.; Rooks, D.; Rondon, J.C.; Roubenoff, R. Effects of bimagrumab, an activin receptor type II inhibitor, on pituitary neurohormonal axes. Clin. Endocrinol. 2018, 88, 908–919.
  159. Pabla, N.; Dong, Z. Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int. 2008, 73, 994–1007.
  160. Castonguay, R.; Lachey, J.; Wallner, S.; Strand, J.; Liharska, K.; Watanabe, A.E.; Cannell, M.; Davies, M.V.; Sako, D.; Troy, M.E. Follistatin-288-Fc fusion protein promotes localized growth of skeletal muscle. J. Pharmacol. Exp. Ther. 2019, 368, 435–445.
  161. Cash, J.N.; Rejon, C.A.; McPherron, A.C.; Bernard, D.J.; Thompson, T.B. The structure of myostatin: Follistatin 288: Insights into receptor utilization and heparin binding. EMBO J. 2009, 28, 2662–2676.
  162. Lerch, T.F.; Shimasaki, S.; Woodruff, T.K.; Jardetzky, T.S. Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions. J. Biol. Chem. 2007, 282, 15930–15939.
  163. Wang, E.Y.; Draper, L.B.; Lee, E.; Polak, A.; Sluss, P.; Weiss, J.; Woodruff, T.K. Identification of naturally occurring follistatin complexes in human biological fluids. Biol. Reprod. 1999, 60, 8–13.
  164. Schneyer, A.L.; Wang, Q.; Sidis, Y.; Sluss, P.M. Differential distribution of follistatin isoforms: Application of a new FS315-specific immunoassay. J. Clin. Endocrinol. Metab. 2004, 89, 5067–5075.
  165. Thompson, T.B.; Lerch, T.F.; Cook, R.W.; Woodruff, T.K.; Jardetzky, T.S. The structure of the follistatin: Activin complex reveals antagonism of both type I and type II receptor binding. Dev. Cell 2005, 9, 535–543.
  166. Sidis, Y.; Mukherjee, A.; Keutmann, H.; Delbaere, A.; Sadatsuki, M.; Schneyer, A. Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins. J. Endocrinol. 2006, 147, 3586–3597.
  167. Hashimoto, O.; Nakamura, T.; Shoji, H.; Shimasaki, S.; Hayashi, Y.; Sugino, H. A novel role of follistatin, an activin-binding protein, in the inhibition of activin action in rat pituitary cells: Endocytotic degradation of activin and its acceleration by follistatin associated with cell-surface heparan sulfate. J. Biol. Chem. 1997, 272, 13835–13842.
  168. Jones, K.L.; Mansell, A.; Patella, S.; Scott, B.J.; Hedger, M.P.; de Kretser, D.M.; Phillips, D.J. Activin A is a critical component of the inflammatory response, and its binding protein, follistatin, reduces mortality in endotoxemia. Proc. Natl. Acad. Sci. USA 2007, 104, 16239–16244.
  169. Hidalgo, I.J.; Raub, T.J.; Borchardt, R.T. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 1989, 96, 736–749.
  170. Moustakas, A.; Kardassis, D. Regulation of the human p21/WAF1/Cip1 promoter in hepatic cells by functional interactions between Sp1 and Smad family members. Proc. Natl. Acad. Sci. USA 1998, 95, 6733–6738.
  171. Oda, S.; Nishimatsu, S.-I.; Murakami, K.; Ueno, N. Molecular cloning and functional analysis of a new activin β subunit: A dorsal mesoderm-inducing activity in Xenopus. Biochem. Biophys. Res. Commun. 1995, 210, 581–588.
  172. Parker, S.B.; Eichele, G.; Zhang, P.; Rawls, A.; Sands, A.T.; Bradley, A.; Olson, E.N.; Harper, J.W.; Elledge, S.J. p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells. Science 1995, 267, 1024–1027.
  173. Evers, B.M.; Ko, T.C.; Li, J.; Thompson, E.A. Cell cycle protein suppression and p21 induction in differentiating Caco-2 cells. Am. J. Physiol. Gastrointest. Liver Physiol. 1996, 271, G722–G727.
  174. Kogure, K.; Omata, W.; Kanzaki, M.; Zhang, Y.-Q.; Yasuda, H.; Mine, T.; Kojima, I. A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats. Gastroenterology 1995, 108, 1136–1142.
  175. Ishiki, Y.; Ohnishi, H.; Muto, Y.; Matsumoto, K.; Nakamura, T. Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology 1992, 16, 1227–1235.
  176. Staudacher, J.J.; Bauer, J.; Jana, A.; Tian, J.; Carroll, T.; Mancinelli, G.; Özden, Ö.; Krett, N.; Guzman, G.; Kerr, D. Activin signaling is an essential component of the TGF-β induced pro-metastatic phenotype in colorectal cancer. Sci. Rep. 2017, 7, 5569.
  177. Zhang, Y.-Q.; Resta, S.; Jung, B.; Barrett, K.E.; Sarvetnick, N. Upregulation of activin signaling in experimental colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2009, 297, G768–G780.
  178. Stoitzner, P.; Stössel, H.; Wankell, M.; Hofer, S.; Heufler, C.; Werner, S.; Romani, N. Langerhans cells are strongly reduced in the skin of transgenic mice overexpressing follistatin in the epidermis. Eur. J. Cell Biol. 2005, 84, 733–741.
  179. Yaden, B.C.; Croy, J.E.; Wang, Y.; Wilson, J.M.; Datta-Mannan, A.; Shetler, P.; Milner, A.; Bryant, H.U.; Andrews, J.; Dai, G. Follistatin: A novel therapeutic for the improvement of muscle regeneration. J. Pharmacol. Exp. Ther. 2014, 349, 355–371.
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