Advances in understanding the role of cytokines in inflammatory bowel disease

ABSTRACT Introduction: Cytokines represent the key pathophysiologic elements that govern the initiation, progression, and, in some circumstances, the resolution of the inflammation occurring in inflammatory bowel disease (IBD). Areas covered: In this review, we will focus on the main effector and anti-inflammatory cytokines produced in IBD and discuss the results of recent trials in which cytokine-based therapy has been used for treating IBD patients. Expert commentary: The possibility to sample mucosal biopsies from IBD patients and analyze which molecular pathways are prominent during the active phases of the disease and the easy access to various models of experimental colitis has largely advanced our understanding about the role of cytokines in IBD. These progresses have facilitated the development of several therapeutic compounds, which either target inflammatory cytokines or enhance the regulatory function of immunosuppressive cytokines. While some of such drugs are effective in the induction and maintenance of remission of the disease, other compounds are not useful for attenuating the ongoing mucosal inflammation, thus establishing a hierarchical scale of the relevance of cytokines in IBD. Further work is needed to identify biomarkers, which could help personalize cytokine-targeted therapy and minimize potential side effects.

[1]  T. Macdonald,et al.  Regulation of homeostasis and inflammation in the intestine. , 2011, Gastroenterology.

[2]  A. Andoh,et al.  Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. , 2004, Clinical immunology.

[3]  Marc Vandemeulebroecke,et al.  Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial , 2012, Gut.

[4]  G PLACITELLI,et al.  [Ulcerative colitis]. , 1958, La Riforma medica.

[5]  W. Sandborn,et al.  A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. , 2014, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[6]  T. Sakaguchi,et al.  Claudins regulate the intestinal barrier in response to immune mediators. , 2000, Gastroenterology.

[7]  T. Hibi,et al.  IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease , 2008, Gut.

[8]  T. Denning,et al.  CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation and colitogenic TH17 responses in mice , 2011, The Journal of clinical investigation.

[9]  S. Hanauer,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group , 2022 .

[10]  R. Flavell,et al.  CD4 T-cell differentiation and inflammatory bowel disease. , 2009, Trends in molecular medicine.

[11]  M. Marinaro,et al.  Inhibition of Smad7 with a specific antisense oligonucleotide facilitates TGF-beta1-mediated suppression of colitis. , 2006, Gastroenterology.

[12]  R. Xavier,et al.  IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. , 2008, The Journal of clinical investigation.

[13]  A. Hartmann,et al.  IL-9 and its receptor are predominantly involved in the pathogenesis of UC , 2014, Gut.

[14]  C. Fiocchi,et al.  Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis , 2010, Proceedings of the National Academy of Sciences.

[15]  K. Patra,et al.  Efficacy and Safety of MEDI2070, an Antibody Against Interleukin 23, in Patients With Moderate to Severe Crohn's Disease: A Phase 2a Study. , 2017, Gastroenterology.

[16]  N. Beauchemin,et al.  Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. , 2010, Immunity.

[17]  A. Andoh,et al.  Epithelial expression of interleukin‐37b in inflammatory bowel disease , 2013, Clinical and experimental immunology.

[18]  Markus F. Neurath,et al.  Cytokines in inflammatory bowel disease , 2014, Nature Reviews Immunology.

[19]  Paul Rutgeerts,et al.  Infliximab for induction and maintenance therapy for ulcerative colitis. , 2005, The New England journal of medicine.

[20]  P. Rutgeerts,et al.  A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease , 2005, Gut.

[21]  B. Müller-Myhsok,et al.  Role of the novel Th17 cytokine IL‐17F in inflammatory bowel disease (IBD): Upregulated colonic IL‐17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD , 2008, Inflammatory bowel diseases.

[22]  Francis J. Huber,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. , 2011, Immunity.

[23]  M. Good,et al.  IL‐33 and the intestine: The good, the bad, and the inflammatory , 2017, Cytokine.

[24]  A. Foussat,et al.  Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. , 2012, Gastroenterology.

[25]  B. Becher,et al.  RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. , 2009, Gastroenterology.

[26]  C. Abraham,et al.  TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. , 2013, Gastroenterology.

[27]  Jay K Kolls,et al.  The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. , 2013, Annual review of pathology.

[28]  T. Mcclanahan,et al.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. , 2006, The Journal of clinical investigation.

[29]  Judy H. Cho,et al.  The genetics and immunopathogenesis of inflammatory bowel disease , 2008, Nature Reviews Immunology.

[30]  W. Sandborn,et al.  Crohn's disease , 2012, The Lancet.

[31]  Linheng Li,et al.  Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. , 2010, Immunity.

[32]  D. Podolsky,et al.  Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. , 1996, Gastroenterology.

[33]  P. Zhu,et al.  Interleukin-33 Ameliorates Experimental Colitis through Promoting Th2/Foxp3+ Regulatory T-Cell Responses in Mice , 2012, Molecular medicine.

[34]  The Transcription Factor T-bet Regulates Mucosal T Cell Activation in Experimental Colitis and Crohn's Disease , 2002, The Journal of Experimental Medicine.

[35]  A. Forbes,et al.  Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn's disease , 2001, Gut.

[36]  O. Nielsen,et al.  Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. , 2013, Pharmacological research.

[37]  A. Fusco,et al.  Bioactive IL-18 expression is up-regulated in Crohn's disease. , 1999, Journal of immunology.

[38]  S. Siakavellas,et al.  Role of the IL-23/IL-17 axis in Crohn's disease. , 2012, Discovery medicine.

[39]  P. Rutgeerts,et al.  Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease , 2000 .

[40]  T. Hibi,et al.  A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. , 2004, Gastroenterology.

[41]  R. Flavell,et al.  Transforming Growth Factor-β Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell-Dependent and -Independent Mechanisms , 2006 .

[42]  T. Mcclanahan,et al.  Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. , 2007, Gastroenterology.

[43]  C. FordAlexander,et al.  ULCERATIVE colitis. , 1997, Journal of the American Medical Association.

[44]  C. Hofmann,et al.  IL‐33 attenuates development and perpetuation of chronic intestinal inflammation , 2012, Inflammatory bowel diseases.

[45]  P. Rutgeerts,et al.  Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. , 2016, The New England journal of medicine.

[46]  T. Macdonald,et al.  Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. , 2001, The Journal of clinical investigation.

[47]  R. Xavier,et al.  Unravelling the pathogenesis of inflammatory bowel disease , 2007, Nature.

[48]  H. D. de Souza,et al.  Etiopathogenesis of inflammatory bowel disease: today and tomorrow. , 2017, Current opinion in gastroenterology.

[49]  M. J. Lozano,et al.  Emergence of Inflammatory Bowel Disease During Treatment With Secukinumab , 2018 .

[50]  H. Souza Etiopathogenesis of inflammatory bowel disease: today and tomorrow. , 2017 .

[51]  W. Sandborn,et al.  Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. , 2017, The New England journal of medicine.

[52]  R. Flavell,et al.  Transforming growth factor-β in T-cell biology , 2002, Nature Reviews Immunology.

[53]  A. Murphy,et al.  Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. , 2008, Immunity.

[54]  D. Laukens,et al.  Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease , 2010, BMC Immunology.

[55]  M. Neurath,et al.  Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo , 2000, Nature Medicine.

[56]  M. Neurath,et al.  Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. , 2009, Gastroenterology.

[57]  M. Neurath,et al.  Mucosal healing in inflammatory bowel diseases: a systematic review , 2012, Gut.

[58]  A. Rudensky,et al.  CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner , 2009, Science.

[59]  O. Harrison,et al.  Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine , 2015, Mucosal Immunology.

[60]  J. Colombel,et al.  Review article: predictors of response to vedolizumab and ustekinumab in inflammatory bowel disease , 2018, Alimentary pharmacology & therapeutics.

[61]  S. Hanauer,et al.  Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial , 2007, Gut.

[62]  S. Schreiber,et al.  Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial , 2017, The Lancet.

[63]  F. Powrie,et al.  Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells , 2010, Immunity.

[64]  W. Sandborn,et al.  Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. , 2012, The New England journal of medicine.

[65]  T. Moseley,et al.  Interleukin-17 family and IL-17 receptors. , 2003, Cytokine & growth factor reviews.

[66]  S. Targan,et al.  A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of Brodalumab in Patients With Moderate-to-Severe Crohn’s Disease , 2016, The American Journal of Gastroenterology.

[67]  R. Owens,et al.  Oncostatin M drives intestinal inflammation in mice and its abundance predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease , 2017, Nature Medicine.

[68]  Maria Fichera,et al.  Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease. , 2015, The New England journal of medicine.

[69]  G. Fantuzzi,et al.  Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-γ and TNF-α production , 2001 .

[70]  Li Zhang,et al.  IL‐33 induces both regulatory B cells and regulatory T cells in dextran sulfate sodium‐induced colitis , 2017, International immunopharmacology.

[71]  W. Reinisch,et al.  Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study , 2015, Gut.

[72]  G. Sancesario,et al.  Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[73]  Erik Remaut,et al.  A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[74]  G. Morrone,et al.  Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. , 1997, Gastroenterology.

[75]  Yue Zhang,et al.  Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a T(h)17-independent manner. , 2007, International immunology.

[76]  A. Rudensky,et al.  Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. , 2011, Immunity.

[77]  M. Neurath,et al.  Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. , 1996, Journal of immunology.

[78]  D. McGovern,et al.  Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility , 2016, Expert review of clinical immunology.

[79]  T. Macdonald,et al.  Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. , 2005, Gastroenterology.

[80]  Lori A. Coburn,et al.  IL-33 Signaling Protects from Murine Oxazolone Colitis by Supporting Intestinal Epithelial Function , 2015, Inflammatory bowel diseases.

[81]  M. Neurath,et al.  Treatment of T Cell-Dependent Experimental Colitis in SCID Mice by Local Administration of an Adenovirus Expressing IL-18 Antisense mRNA1 , 2002, The Journal of Immunology.

[82]  L. Biancone,et al.  Distinct Profiles of Effector Cytokines Mark the Different Phases of Crohn’s Disease , 2013, PloS one.

[83]  S. Ng,et al.  Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn's disease , 2011, Inflammatory bowel diseases.

[84]  Richard A Flavell,et al.  A protective function for interleukin 17A in T cell–mediated intestinal inflammation , 2009, Nature Immunology.

[85]  A. Griffiths,et al.  Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients. , 2017, Gastroenterology.

[86]  S. Akira,et al.  Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. , 2001, Gastroenterology.

[87]  P. Mannon,et al.  Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. , 2004, The Journal of clinical investigation.

[88]  B. Palmer,et al.  Interleukin 37 is a fundamental inhibitor of innate immunity , 2010, Nature Immunology.

[89]  J. Kolls,et al.  Critical role of IL‐17 receptor signaling in acute TNBS‐induced colitis , 2006, Inflammatory bowel diseases.

[90]  Nirmal Singh,et al.  A Review on Chemical-Induced Inflammatory Bowel Disease Models in Rodents , 2014, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[91]  R. Broaddus,et al.  Regulation of inflammatory responses by IL-17F , 2008, The Journal of experimental medicine.

[92]  A. Kaser,et al.  Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study , 2017, The Lancet.

[93]  S. Vermeire,et al.  Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis , 2017, The New England journal of medicine.

[94]  F. Powrie,et al.  Interleukin-23 Restrains Regulatory T Cell Activity to Drive T Cell-Dependent Colitis , 2008, Immunity.

[95]  A. Andoh,et al.  Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis , 2010, Journal of Gastroenterology.

[96]  Ping-Chang Yang,et al.  The increased expression of IL‐23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity , 2011, Journal of leukocyte biology.

[97]  L. Peyrin-Biroulet,et al.  Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study , 2014, Gut.

[98]  C. Dinarello,et al.  Interleukin 37 expression protects mice from colitis , 2011, Proceedings of the National Academy of Sciences.

[99]  M. Leach,et al.  T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice , 1996, The Journal of experimental medicine.

[100]  M. Zeitz,et al.  Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. , 2005, Gastroenterology.

[101]  H. Turnquist,et al.  IL-33 Is an Unconventional Alarmin That Stimulates IL-2 Secretion by Dendritic Cells To Selectively Expand IL-33R/ST2+ Regulatory T Cells , 2014, The Journal of Immunology.

[102]  H. Kiyono,et al.  Colitis in mice lacking the common cytokine receptor gamma chain is mediated by IL-6-producing CD4+ T cells. , 2005, Gastroenterology.

[103]  R. D. Hatton,et al.  IL-17 family cytokines and the expanding diversity of effector T cell lineages. , 2007, Annual review of immunology.

[104]  P. Rutgeerts,et al.  Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. , 2006, Gastroenterology.

[105]  M. Kastan,et al.  The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. , 2010, Immunity.

[106]  S. Brand,et al.  Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment , 2013, Gut.

[107]  T. Macdonald,et al.  Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21 , 2006, Gut.

[108]  R. Blumberg,et al.  The immunology of mucosal models of inflammation. , 2002, Annual review of immunology.

[109]  G. Corazza,et al.  Absence of a role for interleukin‐13 in inflammatory bowel disease , 2014, European journal of immunology.

[110]  G. Greenberg,et al.  Ustekinumab induction and maintenance therapy in refractory Crohn's disease. , 2012, The New England journal of medicine.