Abstract
Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the destructive power of aggressive microbiota in the gut lumen.
Many cytokines have been found upregulated in patients with inflammatory bowel diseases in correlation with disease activity. A central role seem to play cytokines that coordinate the T helper cell response. Although big scientific efforts have been made until today, only TNF blockers reached the clinical routine and many anti-cytokine strategies were only effective in rodent models of colitis. This chapter gives an overview about relevant pathomechanisms in mucosal immunology of the gut and focuses on the key cytokines that have been identified as targets for novel therapeutic strategies in human IBD.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Eissner G, Kolch W, Scheurich P (2004) Ligands working as receptors: reverse signaling by members of the TNF superfamily enhance the plasticity of the immune system. Cytokine Growth Factor Rev 15(5):353–366, Epub 2004/09/29
Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10(1):45–65
Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P et al (1994) Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 106(6):1455–1466
Murch SH, Braegger CP, Walker-Smith JA, MacDonald TT (1993) Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 34(12):1705–1709
Neurath MF, Meyer zum Buschenfelde KH (1996) Protective and pathogenic roles of cytokines in inflammatory bowel diseases. J Investig Med 44(9):516–521
Reimund JM, Wittersheim C, Dumont S, Muller CD, Baumann R, Poindron P et al (1996) Mucosal inflammatory cytokine production by intestinal biopsies in patients with ulcerative colitis and Crohn’s disease. J Clin Immunol 16(3):144–150
Sartor RB (1994) Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology 106(2):533–539
MacDonald TT, Hutchings P, Choy MY, Murch S, Cooke A (1990) Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol 81(2):301–305, Epub 1990/08/01
Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA et al (1999) Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 340(18):1398–1405
Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T (2001) Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 121(5):1145–1157
ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJ (2002) Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 50(2):206–211
Shen C, Assche GV, Colpaert S, Maerten P, Geboes K, Rutgeerts P et al (2005) Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 21(3):251–258
Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D et al (2007) Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med 357(3):228–238, Epub 2007/07/20
Nesbitt A, Fossati G, Bergin M, Stephens P, Stephens S, Foulkes R et al (2007) Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 13(11):1323–1332
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(6):2026–2038
Rutgeerts P, Van Assche G, Vermeire S (2006) Review article: Infliximab therapy for inflammatory bowel disease—seven years on. Aliment Pharmacol Ther 23(4):451–463
Afif W, Loftus EV Jr, Faubion WA, Kane SV, Bruining DH, Hanson KA et al (2010) Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 105(5):1133–1139
Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH et al (2004) Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2(7):542–553, Epub 2004/06/30
Baert F, Noman M, Vermeire S, Van Assche G, D’ Haens G, Carbonez A et al (2003) Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 348(7):601–608
Maser EA, Villela R, Silverberg MS, Greenberg GR (2006) Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn's disease. Clin Gastroenterol Hepatol 4(10):1248–1254
Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P (2003) Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 124(4):917–924
Van Bockstaele F, Holz JB, Revets H (2009) The development of nanobodies for therapeutic applications. Curr Opin Investig Drugs 10(11):1212–1224
Semerano L, Assier E, Delavallee L, Boissier MC (2011) Kinoid of human tumor necrosis factor-alpha for rheumatoid arthritis. Expert Opin Biol Ther 11(4):545–550, Epub 2011/03/10
Cappello M, Keshav S, Prince C, Jewell DP, Gordon S (1992) Detection of mRNAs for macrophage products in inflammatory bowel disease by in situ hybridisation. Gut 33(9):1214–1219, Epub 1992/09/01
Mayer L. Inflammatory Bowel Disease, 5th ed., Kirsner JB ed., Philadelphia: W. B. Saunders Company 2000;280–296
Fantini MC, Monteleone G, Macdonald TT (2007) New players in the cytokine orchestra of inflammatory bowel disease. Inflamm Bowel Dis 13(11):1419–1423
Strober W, Fuss IJ (2011) Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 140(6):1756–1767
Pender SL, MacDonald TT (2004) Matrix metalloproteinases and the gut—new roles for old enzymes. Curr Opin Pharmacol 4(6):546–550
Atreya I, Atreya R, Neurath MF (2008) NF-kappaB in inflammatory bowel disease. J Intern Med 263(6):591–596
Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S et al (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446(7135):557–561, Epub 2007/03/16
Gross V, Andus T, Caesar I, Roth M, Scholmerich J (1992) Evidence for continuous stimulation of interleukin-6 production in Crohn’s disease. Gastroenterology 102(2):514–519
Hyams JS, Fitzgerald JE, Treem WR, Wyzga N, Kreutzer DL (1993) Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology 104(5):1285–1292
Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S et al (2000) 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. Nat Med 6(5):583–588
Louis E, Belaiche J, van Kemseke C, Franchimont D, de Groote D, Gueenen V et al (1997) A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn’s disease. Eur J Gastroenterol Hepatol 9(10):939–944
Van Kemseke C, Belaiche J, Louis E (2000) Frequently relapsing Crohn’s disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission. Int J Colorectal Dis 15(4):206–210
Hosokawa T, Kusugami K, Ina K, Ando T, Shinoda M, Imada A et al (1999) Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease. J Gastroenterol Hepatol 14(10):987–996, Epub 1999/10/26
Jostock T, Mullberg J, Ozbek S, Atreya R, Blinn G, Voltz N et al (2001) Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 268(1):160–167
Mitsuyama K, Toyonaga A, Sasaki E, Ishida O, Ikeda H, Tsuruta O et al (1995) Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut 36(1):45–49
de Jong YP, Abadia-Molina AC, Satoskar AR, Clarke K, Rietdijk ST, Faubion WA et al (2001) Development of chronic colitis is dependent on the cytokine MIF. Nat Immunol 2(11):1061–1066
Holub MC, Mako E, Devay T, Dank M, Szalai C, Fenyvesi A et al (1998) Increased interleukin-6 levels, interleukin-6 receptor and gp130 expression in peripheral lymphocytes of patients with inflammatory bowel disease. Scand J Gastroenterol Suppl 228:47–50
Ina K, Itoh J, Fukushima K, Kusugami K, Yamaguchi T, Kyokane K et al (1999) Resistance of Crohn’s disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol 163(2):1081–1090
Ishiguro Y (1999) Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis. J Gastroenterol 34(1):66–74, Epub 1999/04/16
Iimura M, Nakamura T, Shinozaki S, Iizuka B, Inoue Y, Suzuki S et al (2000) Bax is downregulated in inflamed colonic mucosa of ulcerative colitis. Gut 47(2):228–235
Mitsuyama K, Sata M, Rose-John S (2006) Interleukin-6 trans-signaling in inflammatory bowel disease. Cytokine Growth Factor Rev 17(6):451–461
Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A et al (2004) A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 126(4):989–996, discussion 47
Strober W, Fuss I, Mannon P (2007) The fundamental basis of inflammatory bowel disease. J Clin Invest 117(3):514–521
Strober W, Fuss IJ, Blumberg RS (2002) The immunology of mucosal models of inflammation. Annu Rev Immunol 20:495–549
Meng G, Zhang F, Fuss I, Kitani A, Strober W (2009) A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30(6):860–874
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189
Prehn JL, Thomas LS, Landers CJ, Yu QT, Michelsen KS, Targan SR (2007) The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. J Immunol 178(7):4033–4038
Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Takayama T et al (2010) TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn’s disease. Inflamm Bowel Dis 16(4):568–575
Meylan F, Song YJ, Fuss I, Villarreal S, Kahle E, Malm IJ et al (2011) The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal Immunol 4(2):172–185
Takedatsu H, Michelsen KS, Wei B, Landers CJ, Thomas LS, Dhall D et al (2008) TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology 135(2):552–567
Schreiber TH, Wolf D, Tsai MS, Chirinos J, Deyev VV, Gonzalez L et al (2010) Therapeutic Treg expansion in mice by TNFRSF25 prevents allergic lung inflammation. J Clin Invest 120(10):3629–3640
Bamias G, Martin C III, Marini M, Hoang S, Mishina M, Ross WG et al (2003) Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol 171(9):4868–4874
Prehn JL, Mehdizadeh S, Landers CJ, Luo X, Cha SC, Wei P et al (2004) Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clin Immunol 112(1):66–77
Duchmann R, Lochs H, Kruis W (1999) Morbus Crohn, Colitis ulcerosa. Wenn Bakterien die Darmwand attackieren.... [Crohn disease, ulcerative colitis. When bacteria attack the intestinal wall....]. MMW Fortschritte der Medizin 141(51–52):48–51. Epub 2000/08/19
Neurath MF, Fuss I, Kelsall BL, Stuber E, Strober W (1995) Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med 182(5):1281–1290
Davidson NJ, Hudak SA, Lesley RE, Menon S, Leach MW, Rennick DM (1998) IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol 161(6):3143–3149
Fuss IJ, Marth T, Neurath MF, Pearlstein GR, Jain A, Strober W (1999) Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice. Gastroenterology 117(5):1078–1088
Neurath MF, Finotto S, Fuss I, Boirivant M, Galle PR, Strober W (2001) Regulation of T-cell apoptosis in inflammatory bowel disease: to die or not to die, that is the mucosal question. Trends Immunol 22(1):21–26
Goriely S, Neurath MF, Goldman M (2008) How microorganisms tip the balance between interleukin-12 family members. Nat Rev Immunol 8(1):81–86
Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R et al (2006) Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25(2):309–318
Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D et al (2004) Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 351(20):2069–2079
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(4):1130–1141
Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B et al (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13(5):715–725
Bettelli E, Oukka M, Kuchroo VK (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8(4):345–350
Ivanov II, Zhou L, Littman DR (2007) Transcriptional regulation of Th17 cell differentiation. Semin Immunol 19(6):409–417
McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10(3):314–324
McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T et al (2007) 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 8(12):1390–1397
Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS et al (2006) Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 203(11):2473–2483
Burakoff R, Barish CF, Riff D, Pruitt R, Chey WY, Farraye FA et al (2006) A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn’s disease. Inflamm Bowel Dis 12(7):558–565
Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S, Louis E et al (2007) An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum Mol Genet 16(24):3008–3016, Epub 2007/09/21
Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L et al (2008) Regulation of inflammatory responses by IL-17F. J Exp Med 205(5):1063–1075
Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C et al (2009) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136(1):257–267
O'Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y et al (2009) A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10(6):603–609
Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK (2006) Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 12(5):382–388
Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14(2):155–174
Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ et al (2010) Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33(2):279–288, Epub 2010/08/25
Reinisch W, de Villiers W, Bene L, Simon L, Racz I, Katz S et al (2010) Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm Bowel Dis 16(2):233–242
Reinisch W, Hommes DW, Van Assche G, Colombel JF, Gendre JP, Oldenburg B et al (2006) A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn’s disease. Gut 55(8):1138–1144
Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B et al (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204(8):1849–1861
Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, Desai B et al (2010) Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. J Immunol 185(1):679–687
Lee YK, Mukasa R, Hatton RD, Weaver CT (2009) Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol 21(3):274–280
Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupe P, Barillot E et al (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol 9(6):650–657
Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F et al (1997) Interleukin 12 is expressed and actively released by Crohn’s disease intestinal lamina propria mononuclear cells. Gastroenterology 112(4):1169–1178
Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT (2001) Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 108(4):601–609
Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S et al (2005) Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn’s disease but not in ulcerative colitis. Inflamm Bowel Dis 11(1):16–23
Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T et al (2010) TGF-beta induces IL-9 production from human Th17 cells. J Immunol 185(1):46–54
Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453(7198):1051–1057
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517
Stephens GL, Swerdlow B, Benjamin E, Coyle AJ, Humbles A, Kolbeck R et al (2011) IL-9 is a Th17-derived cytokine that limits pathogenic activity in organ-specific autoimmune disease. Eur J Immunol 41(4):952–962
Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F et al (2008) Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology 134(4):1038–1048
Monteleone G, Monteleone I, Fina D, Vavassori P, Del Vecchio BG, Caruso R et al (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease. Gastroenterology 128(3):687–694
Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT et al (2007) IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 178(2):732–739
Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C et al (2006) Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut 55(12):1774–1780
Caruso R, Fina D, Peluso I, Stolfi C, Fantini MC, Gioia V et al (2007) A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. Gastroenterology 132(1):166–175
Izcue A, Hue S, Buonocore S, Arancibia-Carcamo CV, Ahern PP, Iwakura Y et al (2008) Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28(4):559–570
Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD et al (2012) 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. Gut 61(12):1693–1700
Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK et al (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118(2):534–544
Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206(7):1465–1472
Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM et al (2006) 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 290(4):G827–G838
Cox JH, Kljavin NM, Ramamoorthi N, Diehl L, Batten M, Ghilardi N (2011) IL-27 promotes T cell-dependent colitis through multiple mechanisms. J Exp Med 208(1):115–123
Wirtz S, Tubbe I, Galle PR, Schild HJ, Birkenbach M, Blumberg RS et al (2006) Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med 203(8):1875–1881
Bruewer M, Luegering A, Kucharzik T, Parkos CA, Madara JL, Hopkins AM et al (2003) Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms. J Immunol 171(11):6164–6172
Leaphart CL, Dai S, Gribar SC, Richardson W, Ozolek J, Shi XH et al (2008) Interferon-gamma inhibits enterocyte migration by reversibly displacing connexin43 from lipid rafts. Am J Physiol Gastrointest Liver Physiol 295(3):G559–G569
Leaphart CL, Qureshi F, Cetin S, Li J, Dubowski T, Baty C et al (2007) Interferon-gamma inhibits intestinal restitution by preventing gap junction communication between enterocytes. Gastroenterology 132(7):2395–2411
Tong Q, Vassilieva EV, Ivanov AI, Wang Z, Brown GT, Parkos CA et al (2005) Interferon-gamma inhibits T84 epithelial cell migration by redirecting transcytosis of beta1 integrin from the migrating leading edge. J Immunol 175(6):4030–4038
The_MHC_Consortium (1999) Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium. Nature 401(6756):921–923, Epub 1999/11/30
Colgan SP, Parkos CA, Matthews JB, D'Andrea L, Awtrey CS, Lichtman AH et al (1994) Interferon-gamma induces a cell surface phenotype switch on T84 intestinal epithelial cells. Am J Physiol 267(2 Pt 1):C402–C410
Ruemmele FM, Gurbindo C, Mansour AM, Marchand R, Levy E, Seidman EG (1998) Effects of interferon gamma on growth, apoptosis, and MHC class II expression of immature rat intestinal crypt (IEC-6) cells. J Cell Physiol 176(1):120–126
Diegelmann J, Olszak T, Goke B, Blumberg RS, Brand S (2012) A novel role for interleukin-27 (IL-27) as mediator of intestinal epithelial barrier protection mediated via differential signal transducer and activator of transcription (STAT) protein signaling and induction of antibacterial and anti-inflammatory proteins. J Biol Chem 287(1):286–298
Sasaoka T, Ito M, Yamashita J, Nakajima K, Tanaka I, Narita M et al (2011) Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. Am J Physiol Gastrointest Liver Physiol 300(4):G568–G576
Wirtz S, Billmeier U, McHedlidze T, Blumberg RS, Neurath MF (2011) Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology 141(5):1875–1886
Jacobo EM, Dario FM, Kathleen SH (2000) Behavioral and psychological signs and symptoms of dementia: a practicing psychiatrist’s viewpoint. Dialogues Clin Neurosci 2(2):139–155, Epub 2000/06/01
Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F et al (2006) Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 12(1):9–15
Hart AL, Al-Hassi HO, Rigby RJ, Bell SJ, Emmanuel AV, Knight SC et al (2005) Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology 129(1):50–65
Matsuoka K, Inoue N, Sato T, Okamoto S, Hisamatsu T, Kishi Y et al (2004) T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease. Gut 53(9):1303–1308
Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S et al (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Invest 113(10):1490–1497
Mannon PJ, Hornung RL, Yang Z, Yi C, Groden C, Friend J et al (2011) Suppression of inflammation in ulcerative colitis by interferon-beta-1a is accompanied by inhibition of IL-13 production. Gut 60(4):449–455
Hoyer KK, Dooms H, Barron L, Abbas AK (2008) Interleukin-2 in the development and control of inflammatory disease. Immunol Rev 226:19–28
Balzano A, Bove A, Leonardi E, Bevilacqua N, Grande G, Ascierto PA et al (1997) The soluble interleukin-2 receptor as an indicator of clinical evolution in patients with ulcerative colitis. Eur J Gastroenterol Hepatol 9(2):173–177
Nielsen OH, Ciardelli T, Wu Z, Langholz E, Kirman I (1995) Circulating soluble interleukin-2 receptor alpha and beta chain in inflammatory bowel disease. Am J Gastroenterol 90(8):1301–1306
Van Assche G, Dalle I, Noman M, Aerden I, Swijsen C, Asnong K et al (2003) A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol 98(2):369–376
Creed TJ, Norman MR, Probert CS, Harvey RF, Shaw IS, Smithson J et al (2003) Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis. Aliment Pharmacol Ther 18(1):65–75
Creed TJ, Probert CS, Norman MN, Moorghen M, Shepherd NA, Hearing SD et al (2006) Basiliximab for the treatment of steroid-resistant ulcerative colitis: further experience in moderate and severe disease. Aliment Pharmacol Ther 23(10):1435–1442
Van Assche G, Sandborn WJ, Feagan BG, Salzberg BA, Silvers D, Monroe PS et al (2006) Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut 55(11):1568–1574
Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10(3):170–181
Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75(2):263–274
Colombel JF, Rutgeerts P, Malchow H, Jacyna M, Nielsen OH, Rask-Madsen J et al (2001) Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut 49(1):42–46
Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G et al (2000) Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn’s disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology 119(6):1473–1482
Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S et al (2000) Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn’s Disease IL-10 Cooperative Study Group. Gastroenterology 119(6):1461–1472
Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP et al (2006) A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease. Clin Gastroenterol Hepatol 4(6):754–759, Epub 2006/05/24
Vermeire S, Rutgeerts P, D’haens G et al (2010) A Phase 2a Randomized placebo-controlled double-blind multi-center dose escalation study to evaluate the safety, tolerability, pharmacodynamics and effi cacy of AG011 in patients with moderately active ulcerative colitis. Digestive Disease Week. New Orleans, LA, USA
Trepicchio WL, Wang L, Bozza M, Dorner AJ (1997) IL-11 regulates macrophage effector function through the inhibition of nuclear factor-kappaB. J Immunol 159(11):5661–5670
Kiessling S, Muller-Newen G, Leeb SN, Hausmann M, Rath HC, Strater J et al (2004) Functional expression of the interleukin-11 receptor alpha-chain and evidence of antiapoptotic effects in human colonic epithelial cells. J Biol Chem 279(11):10304–10315
Peterson RL, Wang L, Albert L, Keith JC Jr, Dorner AJ (1998) Molecular effects of recombinant human interleukin-11 in the HLA-B27 rat model of inflammatory bowel disease. Lab Invest 78(12):1503–1512
Qiu BS, Pfeiffer CJ, Keith JC Jr (1996) Protection by recombinant human interleukin-11 against experimental TNB-induced colitis in rats. Dig Dis Sci 41(8):1625–1630
Sands BE, Winston BD, Salzberg B, Safdi M, Barish C, Wruble L et al (2002) Randomized, controlled trial of recombinant human interleukin-11 in patients with active Crohn’s disease. Aliment Pharmacol Ther 16(3):399–406
Herrlinger KR, Witthoeft T, Raedler A, Bokemeyer B, Krummenerl T, Schulzke JD et al (2006) Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn’s disease. Am J Gastroenterol 101(4):793–797
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Engel, M.A., Neurath, M.F. (2013). Cytokines in Inflammatory Bowel Disease. In: D'Amato, M., Rioux, J. (eds) Molecular Genetics of Inflammatory Bowel Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8256-7_15
Download citation
DOI: https://doi.org/10.1007/978-1-4614-8256-7_15
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-8255-0
Online ISBN: 978-1-4614-8256-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)