Abstract
Inflammatory bowel diseases are chronic, relapsing, immunologically mediated disorders of the gastrointestinal tract. Emerging evidence suggests a critical functional role of transcription factors and T cell-related cytokines in ulcerative colitis and Crohn’s disease. Gut-residing T cells from patients with inflammatory bowel disease produce high amounts of IL-9. Experimental models of colitis highlighted that IL-9-producing T cells critically interfered with an intact barrier function of the intestinal epithelium by impacting cellular proliferation and tight junction molecules. The blockade of IL-9 was suited to significantly ameliorate the disease activity and severity in experimental models of inflammatory bowel disease thereby suggesting that targeting IL-9 might function as a novel targeted approach for therapy.
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Abbreviations
- CD:
-
Crohn’s disease
- UC:
-
Ulcerative colitis
- IBD:
-
Inflammatory bowel disease
References
Danese S, Fiocchi C (2011) Ulcerative colitis. N Engl J Med 365:1713–1725
Baumgart DC, Sandborn WJ (2012) Crohn's disease. Lancet 380:1590–1605
Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ (2013) Crohn's disease complicated by strictures: a systematic review. Gut 62:1072–1084
Soderlund S, Granath F, Brostrom O, Karlen P, Lofberg R, Ekbom A et al (2010) Inflammatory bowel disease confers a lower risk of colorectal cancer to females than to males. Gastroenterology 138:1697–1703
Thomas T, Abrams KA, Robinson RJ, Mayberry JF (2007) Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther 25:657–668
Kiesslich R, Fritsch J, Holtmann M, Koehler HH, Stolte M, Kanzler S et al (2003) Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 124:880–888
Rutter MD, Saunders BP, Schofield G, Forbes A, Price AB, Talbot IC (2004) Pancolonic indigo carmine dye spraying for the detection of dysplasia in ulcerative colitis. Gut 53:256–260
Rogler G (2013) Chronic ulcerative colitis and colorectal cancer. Cancer Lett 345(2):235–241
Foersch S, Waldner MJ, Neurath MF (2012) Colitis and colorectal cancer. Dig Dis 30:469–476
Bernstein CN, Blanchard JF, Rawsthorne P, Yu N (2001) The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 96:1116–1122
Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ (2011) Long-term complications, extraintestinal manifestations, and mortality in adult Crohn's disease in population-based cohorts. Inflamm Bowel Dis 17:471–478
Agrez MV, Valente RM, Pierce W, Melton LJ 3rd, van Heerden JA, Beart RW Jr (1982) Surgical history of Crohn’s disease in a well-defined population. Mayo Clinic proceedings Mayo Clinic 57:747–752
Danese S, Colombel JF, Peyrin-Biroulet L, Rutgeerts P, Reinisch W (2013) Review article: the role of anti-TNF in the management of ulcerative colitis—past, present and future. Aliment Pharmacol Ther 37:855–866
Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J (2006) Predictors of Crohn’s disease. Gastroenterology 130:650–656
Joossens M, Simoens M, Vermeire S, Bossuyt X, Geboes K, Rutgeerts P (2007) Contribution of genetic and environmental factors in the pathogenesis of Crohn’s disease in a large family with multiple cases. Inflamm Bowel Dis 13:580–584
Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124
Parkes M (2012) The genetics universe of Crohn's disease and ulcerative colitis. Dig Dis 30(Suppl 1):78–81
Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T et al (2016) Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387:156–167
Lakatos PL, Szamosi T, Lakatos L (2007) Smoking in inflammatory bowel diseases: good, bad or ugly? World journal of gastroenterology : WJG 13:6134–6139
Louis E, Michel V, Hugot JP, Reenaers C, Fontaine F, Delforge M et al (2003) Early development of stricturing or penetrating pattern in Crohn’s disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD15 genotype. Gut 52:552–557
Loftus EV Jr (2004) Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 126:1504–1517
Neurath MF (2014) Cytokines in inflammatory bowel disease. Nat Rev Immunol 14:329–342
Kiesslich R, Duckworth CA, Moussata D, Gloeckner A, Lim LG, Goetz M et al (2012) Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel disease. Gut 61:1146–1153
Neurath MF, Finotto S, Glimcher LH (2002) The role of Th1/Th2 polarization in mucosal immunity. Nat Med 8:567–573
Calderon-Gomez E, Bassolas-Molina H, Mora-Buch R, Dotti I, Planell N, Esteller M et al (2016) Commensal-specific CD4(+) cells from patients with Crohn’s disease have a T-Helper 17 inflammatory profile. Gastroenterology 151:489–500 e483
Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR (1987) Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med 166:1229–1244
Ho IC, Tai TS, Pai SY (2009) GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol 9:125–135
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669
Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH (2002) Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295:338–342
Yang XO, Angkasekwinai P, Zhu J, Peng J, Liu Z, Nurieva R et al (2009) Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat Immunol 10:1260–1266
Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH et al (2002) Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295:336–338
Kamada N, Hisamatsu T, Okamoto S, Sato T, Matsuoka K, Arai K et al (2005) Abnormally differentiated subsets of intestinal macrophage play a key role in Th1-dominant chronic colitis through excess production of IL-12 and IL-23 in response to bacteria. J Immunol 175:6900–6908
Uyttenhove C, Simpson RJ, Van Snick J (1988) Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A 85:6934–6938
Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, Rubira MR et al (1989) Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med 169:363–368
Schmitt E, Van Brandwijk R, Van Snick J, Siebold B, Rude E (1989) TCGF III/P40 is produced by naive murine CD4+ T cells but is not a general T cell growth factor. Eur J Immunol 19:2167–2170
Moeller J, Hultner L, Schmitt E, Breuer M, Dormer P (1990) Purification of MEA, a mast cell growth-enhancing activity, to apparent homogeneity and its partial amino acid sequencing. J Immunol 144:4231–4234
Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA et al (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol 9:1347–1355
Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S et al (1994) IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 153:3989–3996
Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252:104–115
Kaplan MH, Hufford MM, Olson MR (2015) The development and in vivo function of T helper 9 cells. Nat Rev Immunol 15:295–307
Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J et al (2008) Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9:1341–1346
Schmitt E, Beuscher HU, Huels C, Monteyne P, van Brandwijk R, van Snick J et al (1991) IL-1 serves as a secondary signal for IL-9 expression. J Immunol 147:3848–3854
Uyttenhove C, Brombacher F, Van Snick J (2010) TGF-beta interactions with IL-1 family members trigger IL-4-independent IL-9 production by mouse CD4(+) T cells. Eur J Immunol 40:2230–2235
Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N et al (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33:192–202
Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL et al (2010) The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11:527–534
Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P et al (1993) Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor. Science 262:1880–1883
Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X et al (1993) Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science 262:1877–1880
Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K et al (1995) Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J 14:3654–3663
Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D et al (2001) Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol 167:1–5
Danese S (2012) New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61:918–932
Strober W, Fuss I, Mannon P (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117:514–521
Zundler S, Schillinger D, Fischer A, Atreya R, Lopez-Posadas R, Watson A et al (2016) Blockade of alphaEbeta7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut. doi:10.1136/gutjnl-2016-312439
Macdonald TT, Monteleone G (2005) Immunity, inflammation, and allergy in the gut. Science 307:1920–1925
Strober W, Zhang F, Kitani A, Fuss I, Fichtner-Feigl S (2010) Proinflammatory cytokines underlying the inflammation of Crohn's disease. Curr Opin Gastroenterol 26:310–317
Atreya R, Neurath MF (2005) Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer. Clinical reviews in allergy & immunology 28:187–196
Atreya R, Zimmer M, Bartsch B, Waldner MJ, Atreya I, Neumann H et al (2011) Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14(+) macrophages. Gastroenterology 141:2026–2038
Neurath MF, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H et al (2002) The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J Exp Med 195:1129–1143
Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA et al (1996) 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 157:1261–1270
Sandborn WJ, Hanauer SB (1999) Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 5:119–133
Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S et al (2008) A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 135:1130–1141
Mudter J, Amoussina L, Schenk M, Yu J, Brustle A, Weigmann B et al (2008) The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J Clin Invest 118:2415–2426
Popp V, Gerlach K, Mott S, Turowska A, Garn H, Atreya R et al (2016) Rectal delivery of a DNAzyme that specifically blocks the transcription factor GATA3 reduces colitis in mice. Gastroenterology. doi:10.1053/j.gastro.2016.09.005
Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S et al (2014) TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15:676–686
Nalleweg N, Chiriac MT, Podstawa E, Lehmann C, Rau TT, Atreya R et al (2015) IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 64:743–755
Murakami-Satsutani N, Ito T, Nakanishi T, Inagaki N, Tanaka A, Vien PT et al (2014) IL-33 promotes the induction and maintanance of Th2 immune response by enhancing the function of OX40 ligand. Allergol Int 63(3):443–455
Blom L, Poulsen BC, Jensen BM, Hansen A, Poulsen LK (2011) IL-33 induces IL-9 production in human CD4+ T cells and basophils. PLoS One 6:e21695
Seidelin JB, Bjerrum JT, Coskun M, Widjaya B, Vainer B, Nielsen OH (2010) IL-33 is upregulated in colonocytes of ulcerative colitis. Immunol Lett 128:80–85
Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, Scarpa M et al (2010) Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S A 107:8017–8022
Defendenti C, Sarzi-Puttini P, Saibeni S, Bollani S, Bruno S, Almasio PL et al (2015) Significance of serum Il-9 levels in inflammatory bowel disease. Int J Immunopathol Pharmacol 28:569–575
Mannon P, Reinisch W (2012) Interleukin 13 and its role in gut defence and inflammation. Gut 61:1765–1773
Wirtz S, Neufert C, Weigmann B, Neurath MF (2007) Chemically induced mouse models of intestinal inflammation. Nat Protoc 2:541–546
Powrie F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL (1994) Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1:553–562
Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL (1996) A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 183:2669–2674
Weigmann B, Lehr HA, Yancopoulos G, Valenzuela D, Murphy A, Stevens S et al (2008) The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J Exp Med 205:2099–2110
Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17:629–638
Kim HS, Chung DH (2013) IL-9-producing invariant NKT cells protect against DSS-induced colitis in an IL-4-dependent manner. Mucosal immunology 6:347–357
Yuan A, Yang H, Qi H, Cui J, Hua W, Li C et al (2015) IL-9 antibody injection suppresses the inflammation in colitis mice. Biochem Biophys Res Commun 468:921–926
Gerlach K, McKenzie AN, Neurath MF, Weigmann B (2015) IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis. Tissue barriers 3:e983777
Acknowledgements
This work was supported in part by the DFG grant WE4656/2-2, SFB 1181/B02 and Clinical Research Unit 257.
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This article is a contribution to the special issue on Th9 Cells in Immunity and Immunopathological Diseases - Guest Editors: Mark Kaplan and Markus Neurath
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Weigmann, B., Neurath, M.F. Th9 cells in inflammatory bowel diseases. Semin Immunopathol 39, 89–95 (2017). https://doi.org/10.1007/s00281-016-0603-z
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DOI: https://doi.org/10.1007/s00281-016-0603-z