Functional relevance of T helper 17 (Th17) cells and the IL-17 cytokine family in inflammatory bowel disease
Gheorghe Hundorfean MD
1st Medical Clinic, University of Erlangen-Nuremberg, Erlangen, Germany
Search for more papers by this authorMarkus F. Neurath MD, PhD
1st Medical Clinic, University of Erlangen-Nuremberg, Erlangen, Germany
Search for more papers by this authorCorresponding Author
Jonas Mudter MD
1st Medical Clinic, University of Erlangen-Nuremberg, Erlangen, Germany
1st Medical Clinic, University of Erlangen-Nürnberg, D-91054 Erlangen, GermanySearch for more papers by this authorGheorghe Hundorfean MD
1st Medical Clinic, University of Erlangen-Nuremberg, Erlangen, Germany
Search for more papers by this authorMarkus F. Neurath MD, PhD
1st Medical Clinic, University of Erlangen-Nuremberg, Erlangen, Germany
Search for more papers by this authorCorresponding Author
Jonas Mudter MD
1st Medical Clinic, University of Erlangen-Nuremberg, Erlangen, Germany
1st Medical Clinic, University of Erlangen-Nürnberg, D-91054 Erlangen, GermanySearch for more papers by this authorAbstract
The recent discovery and characterization of T helper 17 cells (Th17) and their signature cytokines (IL-17) represents a hallmark in T-cell immunobiology by providing a new distinctive pathway for the communication between adaptive and innate immunity. From the six members of the IL-17 cytokine family presently known, at least two have evident proinflammatory qualities and are involved in several chronic inflammatory disorders, including inflammatory bowel disease (IBD). IL-17A and IL-17F are abundantly found in inflamed IBD mucosa, suggesting their pivotal role in IBD. However, the precise implication of IL-17 cytokine family members in IBD pathogenesis and the mechanisms regulating their secretion are incompletely understood. Importantly, recent findings suggest that beyond IL-17 production-Th17 cells may secret a plethora of other effector cytokines such as IL-21, IL-22, and IL-9- which is in part induced by its own IL-9 production. However, the use of anti-IL-17 therapeutic strategies in experimental models of chronic inflammation results in disease-ameliorating effects suggesting their potential use in IBD patients. In this review article we discuss the latest findings on the role of Th17 cells and IL-17 family members in IBD immunopathology, as well as research perspectives. (Inflamm Bowel Dis 2011;)
REFERENCES
- 1 Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med. 2002; 8: 567–573.
- 2 Neurath MF. Immunotherapy of inflammatory bowel diseases: current concepts and future perspectives. Arch Immunol Ther Exp (Warsz). 2000; 48: 81–84.
- 3 Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003; 3: 521–533.
- 4 Colombel JF, Watson AJ, Neurath MF. The 10 remaining mysteries of inflammatory bowel disease. Gut. 2008; 57: 429–433.
- 5 Fuss IJ, Neurath M, Boirivant M, 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. J Immunol. 1996; 157: 1261–1270.
- 6 Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology. 2005; 129: 550–564.
- 7 Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002; 347: 417–429.
- 8 Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314: 1461–1463.
- 9 Mudter J, Neurath MF. Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm Bowel Dis. 2007; 13: 1016–1023.
- 10 Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005; 6: 1123–1132.
- 11 Annunziato F, Cosmi L, Santarlasci V, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007; 204: 1849–1861.
- 12 Cosmi L, De Palma R, Santarlasci V, et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med. 2008; 205: 1903–1916.
- 13 Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease. Gastroenterology. 2009; 137: 1736–1745.
- 14 Nowak EC, Noelle RJ. Interleukin-9 as a T helper type 17 cytokine. Immunology. 2010; 131: 169–173.
- 15 Beriou G, Bradshaw EM, Lozano E, et al. TGF-beta induces IL-9 production from human Th17 cells. J Immunol. 2020; 185: 46–54.
- 16 Fujino S, Andoh A, Bamba S, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003; 52: 65–70.
- 17 Rovedatti L, Kudo T, Biancheri P, et al. Differential regulation of interleukin 17 and interferon gamma production in inflammatory bowel disease. Gut. 2009; 58: 1629–1636.
- 18 Chabaud M, Lubberts E, Joosten L, van Den Berg W, Miossec P. IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arthritis Res. 2001; 3: 168–177.
- 19 Matusevicius D, Kivisakk P, He B, et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999; 5: 101–104.
- 20 Kurasawa K, Hirose K, Sano H, et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 2000; 43: 2455–2463.
- 21 Wong CK, Ho CY, Li EK, Lam CW. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus. 2000; 9: 589–593.
- 22 Linden A. Role of interleukin-17 and the neutrophil in asthma. Int Arch Allergy Immunol. 2001; 126: 179–184.
- 23 Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007; 25: 821–852.
- 24 Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008; 9: 641–649.
- 25 Yang L, Anderson DE, Baecher-Allan C, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature. 2008; 454: 350–352.
- 26 Mangan PR, Harrington LE, O'Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006; 441: 231–234.
- 27 Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature. 2006; 441: 235–238.
- 28 Laurence A, O'Shea JJ. T(H)-17 differentiation: of mice and men. Nat Immunol. 2007; 8: 903–905.
- 29 Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003; 278: 1910–1914.
- 30 Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006; 126: 1121–1133.
- 31 Yang XO, Pappu BP, Nurieva R, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008; 28: 29–39.
- 32 Dambacher J, Beigel F, Zitzmann K, et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 2009; 58: 1207–1217.
- 33 Barnich N, Carvalho FA, Glasser AL, et al. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest. 2007; 117: 1566–1574.
- 34 Niess JH, Leithauser F, Adler G, Reimann J. Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions. J Immunol. 2008; 180: 559–568.
- 35 Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009; 139: 485–498.
- 36 Kleinschek MA, Boniface K, Sadekova S, et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med. 2009; 206: 525–534.
- 37 Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature. 2010; 467: 967–971.
- 38 Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6: 1133–1141.
- 39 Happel KI, Zheng M, Young E, et al. Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol. 2003; 170: 4432–4436.
- 40 Shin HC, Benbernou N, Esnault S, Guenounou M. Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine. 1999; 11: 257–266.
- 41 Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol. 2003; 170: 2106–2112.
- 42 Zhou Q, Desta T, Fenton M, Graves DT, Amar S. Cytokine profiling of macrophages exposed to Porphyromonas gingivalis, its lipopolysaccharide, or its FimA protein. Infect Immun. 2005; 73: 935–943.
- 43 Aggarwal S, Gurney AL. IL-17: prototype member of an emerging cytokine family. J Leukoc Biol. 2002; 71: 1–8.
- 44 Kawaguchi M, Adachi M, Oda N, Kokubu F, Huang SK. IL-17 cytokine family. J Allergy Clin Immunol. 2004; 114: 1265–1273; quiz 1274.
- 45 Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009; 27: 485–517.
- 46 Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol. 1993; 150: 5445–5456.
- 47 Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001; 15: 985–995.
- 48 Hymowitz SG, Filvaroff EH, Yin JP, et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J. 2001; 20: 5332–5341.
- 49 Khalturin K, Panzer Z, Cooper MD, Bosch TC. Recognition strategies in the innate immune system of ancestral chordates. Mol Immunol. 2004; 41: 1077–1087.
- 50 Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004; 21: 467–476.
- 51 Jovanovic DV, Di Battista JA, Martel-Pelletier J, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998; 160: 3513–3521.
- 52 Witowski J, Pawlaczyk K, Breborowicz A, et al. IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GRO alpha chemokine from mesothelial cells. J Immunol. 2000; 165: 5814–5821.
- 53 Fossiez F, Djossou O, Chomarat P, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996; 183: 2593–2603.
- 54 Yao Z, Fanslow WC, Seldin MF, et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995; 3: 811–821.
- 55 Awane M, Andres PG, Li DJ, Reinecker HC. NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells. J Immunol. 1999; 162: 5337–5344.
- 56 Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003; 14: 155–174.
- 57 McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23-IL-17 immune pathway. Trends Immunol. 2006; 27: 17–23.
- 58 Hurst SD, Muchamuel T, Gorman DM, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol. 2002; 169: 443–453.
- 59 Shalom-Barak T, Quach J, Lotz M. Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB. J Biol Chem. 1998; 273: 27467–27473.
- 60 Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med. 2000; 191: 1233–1240.
- 61 Nakae S, Komiyama Y, Nambu A, et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity. 2002; 17: 375–387.
- 62 Nakae S, Nambu A, Sudo K, Iwakura Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol. 2003; 171: 6173–6177.
- 63 Hsu HC, Yang P, Wang J, et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol. 2008; 9: 166–175.
- 64 Korn T, Bettelli E, Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007; 448: 484–487.
- 65 Suto A, Kashiwakuma D, Kagami S, et al. Development and characterization of IL-21-producing CD4+ T cells. J Exp Med. 2008; 205: 1369–1379.
- 66 Zhou L, Ivanov II, Spolski R, et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007; 8: 967–974.
- 67 Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007; 448: 480–483.
- 68 Monteleone G, Monteleone I, Fina D, et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology. 2005; 128: 687–694.
- 69 Caprioli F, Sarra M, Caruso R, et al. Autocrine regulation of IL-21 production in human T lymphocytes. J Immunol. 2008; 180: 1800–1807.
- 70 McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007; 8: 1390–1397.
- 71 Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008; 453: 236–240.
- 72 Brand S, Beigel F, Olszak T, et al. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 2006; 290: G827–838.
- 73 Schmechel S, Konrad A, Diegelmann J, et al. Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis. 2008; 14: 204–212.
- 74 Andoh A, Zhang Z, Inatomi O, et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology. 2005; 129: 969–984.
- 75 Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008; 118: 534–544.
- 76 Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008; 14: 282–289.
- 77 Nowak EC, Weaver CT, Turner H, et al. IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med. 2009; 206: 1653–1660.
- 78 Elyaman W, Bradshaw EM, Uyttenhove C, et al. IL-9 induces differentiation of Th17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009; 106: 12885–12890.
- 79 Seiderer J, Elben I, Diegelmann J, et al. Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease : upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBD. Inflamm Bowel Dis. 2008; 14: 437–445.
- 80 Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol. 2003; 38: 180–185.
- 81 Leppkes M, Becker C, Ivanov II, et al. RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology. 2009; 136: 257–267.
- 82 Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis. 2006; 12: 382–388.
- 83 Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007; 132: 2359–2370.
- 84 Ito R, Kita M, Shin-Ya M, et al. Involvement of IL-17A in the pathogenesis of DSS-induced colitis in mice. Biochem Biophys Res Commun. 2008; 377: 12–16.
- 85 Eberl G, Littman DR. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells. Science. 2004; 305: 248–251.
- 86 Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells. Nat Immunol. 2004; 5: 64–73.
- 87 Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007; 8: 639–646.
- 88 Kobayashi T, Okamoto S, Hisamatsu T, et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut. 2008; 57: 1682–1689.
- 89 Mudter J, Amoussina L, Schenk M, et al. The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J Clin Invest. 2008; 118: 2415–2426.
- 90 Mudter J, Yu J, Amoussina L, et al. IRF4 selectively controls cytokine gene expression in chronic intestinal inflammation. Arch Immunol Ther Exp (Warsz). 2009; 57: 369–376.
- 91 Brustle A, Heink S, Huber M, et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol. 2007; 8: 958–966.
- 92 Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000; 118: 1001–1011.
- 93 Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006; 203: 2271–2279.
- 94 O'Connor W, Jr., Kamanaka M, Booth CJ, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 2009; 10: 603–609.
- 95 Awasthi A, Kuchroo VK. IL-17A directly inhibits Th1 cells and thereby suppresses development of intestinal inflammation. Nat Immunol. 2009; 10: 568–570.
- 96 Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol. 2004; 110: 55–62.
- 97http://clinicaltrials.gov/ct2/show/NCT01009281?term=AIN457&rank=9.
- 98 Huber M, Brustle A, Reinhard K, et al. IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci U S A. 2008; 105: 20846–20851.