Cytokines in inflammatory bowel disease

Key Points

  • Genome-wide association studies have identified several inflammatory bowel disease (IBD) susceptibility loci that contain genes that encode cytokines and proteins involved in cytokine signalling. In particular, recent work has found that loss-of-function mutations in the genes encoding interleukin-10 (IL-10) and the IL-10 receptor are associated with very early-onset IBD.

  • Cytokines not only drive intestinal inflammation and diarrhoea in IBD but may also regulate extra-intestinal disease manifestations (for example, arthralgia or arthritis) and systemic effects. Furthermore, cytokines seem to have a crucial role in driving complications of IBD such as intestinal stenosis, fistula formation and colitis-associated neoplasias.

  • Studies using tissue from patients with IBD and animal models of IBD have identified cytokines as potential new targets for the therapy of intestinal inflammation. Relevant targets include pro-inflammatory cytokines, such as IL-6, IL-12, IL-23 and IL-21, as well as anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β.

  • Anti-cytokine therapies involving tumour necrosis factor (TNF)-specific agents form an important cornerstone of clinical therapy in both Crohn's disease and ulcerative colitis. TNF-specific antibodies suppress chronic intestinal inflammation and may induce mucosal healing in IBD.

  • Several new anti-cytokine agents have shown little or no efficacy in IBD, suggesting the existence of a highly regulated cytokine network. New approaches for anti-cytokine therapies may include multi-cytokine blockers, such as tofacitinib.

  • New cytokine targets, optimized delivery systems for anti-cytokine agents and personalized medicine may pave the way towards more effective clinical approaches by targeting the expression or function of pro-inflammatory and anti-inflammatory cytokines in patients with IBD.

Abstract

Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD.

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Figure 1: Conceptual framework for the pathogenesis of IBD.
Figure 2: Cytokines in the pathogenesis of IBD.
Figure 3: Central role of tumour necrosis factor in the pathogenesis of IBD.
Figure 4: The crucial role of cytokines and epithelial cells on the battlefield: mucosal healing and cancer in IBD.
Figure 5: Cytokine signalling in IBD.

References

  1. 1

    Danese, S. & Fiocchi, C. Ulcerative colitis. New Engl. J. Med. 365, 1713–1725 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Baumgart, D. C. & Sandborn, W. J. Crohn's disease. Lancet 380, 1590–1605 (2012).

    Article  Google Scholar 

  3. 3

    Strober, W., Fuss, I. J. & Blumberg, R. S. The immunology of mucosal models of inflammation. Annu. Rev. Immunol. 20, 495–549 (2002).

    Article  CAS  Google Scholar 

  4. 4

    Powrie, F. et al. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562 (1994). This groundbreaking study defines cytokines as therapeutic targets in chronic intestinal inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Neurath, M. F., Finotto, S. & Glimcher, L. H. The role of Th1/Th2 polarization in mucosal immunity. Nature Med. 8, 567–573 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Ruffolo, C. et al. Subclinical intestinal inflammation in patients with Crohn's disease following bowel resection: a smoldering fire. J. Gastrointestinal Surg. 14, 24–31 (2010).

    Article  Google Scholar 

  7. 7

    Peyrin-Biroulet, L., Loftus, E. V. Jr., Colombel, J. F. & Sandborn, W. J. Long-term complications, extraintestinal manifestations, and mortality in adult Crohn's disease in population-based cohorts. Inflamm. Bowel Dis. 17, 471–478 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21, 491–501 (2004). This study identifies cytokines as a link between inflammation and tumour growth in experimental models of colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Ebert, E. C., Wright, S. H., Lipshutz, W. H. & Hauptman, S. P. T-cell abnormalities in inflammatory bowel disease are mediated by interleukin 2. Clin. Immunol. Immunopathol. 33, 232–244 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Mitsuyama, K., Sata, M. & Tanikawa, K. Significance of interleukin-6 in patients with inflammatory bowel disease. Gastroenterol. Japon. 26, 20–28 (1991).

    Article  CAS  Google Scholar 

  11. 11

    Neurath, M. F., Fuss, I., Kelsall, B. L., Stuber, E. & Strober, W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182, 1281–1290 (1995).

    CAS  Article  Google Scholar 

  12. 12

    Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kotlarz, D. et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143, 347–355 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Tilg, H., Ulmer, H., Kaser, A. & Weiss, G. Role of IL-10 for induction of anemia during inflammation. J. Immunol. 169, 2204–2209 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Herrlinger, K. R. et al. Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease. Am. J. Gastroenterol. 101, 793–797 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Musch, E. et al. Interferon-β-1a for the treatment of steroid-refractory ulcerative colitis: a randomized, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol. 3, 581–586 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    van Dullemen, H. M. et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 109, 129–135 (1995). This study identifies TNF as new therapeutic target in patients with Crohn's disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Danese, S., Colombel, J. F., Peyrin-Biroulet, L., Rutgeerts, P. & Reinisch, W. Review article: the role of anti-TNF in the management of ulcerative colitis — past, present and future. Aliment. Pharmacol. Ther. 37, 855–866 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Neurath, M. F. & Travis, S. P. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 61, 1619–1635 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Reinisch, W. 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. Gut 55, 1138–1144 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Hueber, W. 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. Gut 61, 1693–1700 (2012). This article reveals the unexpected aggravation of Crohn's disease upon neutralization of IL-17A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Ng, S. C. et al. Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn's disease. Inflamm. Bowel Dis 17, 2027–2037 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Casini-Raggi, V. et al. Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J. Immunol. 154, 2434–2440 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Coccia, M. et al. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J. Exp. Med. 209, 1595–1609 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Cominelli, F. et al. Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis. J. Clin. Invest. 86, 972–980 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Kojouharoff, G. et al. Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin. Exp. Immunol. 107, 353–358 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Pizarro, T. T. et al. IL-18, a novel immunoregulatory cytokine, is up-regulated in Crohn's disease: expression and localization in intestinal mucosal cells. J. Immunol. 162, 6829–6835 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Kanai, T. et al. Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. Gastroenterology 121, 875–888 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Siegmund, B. et al. Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-γ and TNF-α production. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1264–R1273 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Atreya, R. 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. Nature Med. 6, 583–588 (2000).

    Article  CAS  Google Scholar 

  31. 31

    Kai, Y. et al. Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4+ T cells. Gastroenterology 128, 922–934 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Ogino, T. et al. Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn's disease. Gastroenterology 145, 1380–1391 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Kamada, N. et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-γ axis. J. Clin. Invest. 118, 2269–2280 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Yamamoto, M., Yoshizaki, K., Kishimoto, T. & Ito, H. IL-6 is required for the development of Th1 cell-mediated murine colitis. J. Immunol. 164, 4878–4882 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Ito, H. et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 126, 989–996 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Atreya, R. et al. 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 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Su, L. et al. TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology 145, 407–415 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Di Sabatino, A. et al. Functional modulation of Crohn's disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology 133, 137–149 (2007). This study defines myofibroblasts as an important target of TNF signalling in IBD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Gunther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Meijer, M. J. et al. Effect of the anti-tumor necrosis factor-α antibody infliximab on the ex vivo mucosal matrix metalloproteinase-proteolytic phenotype in inflammatory bowel disease. Inflamm.Bowel Dis 13, 200–210 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Holtmann, M. H. et al. Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn's disease and promotes experimental colitis in vivo. Eur. J. Immunol. 32, 3142–3151 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Perrier, C. et al. Neutralization of membrane TNF, but not soluble TNF, is crucial for the treatment of experimental colitis. Inflamm. Bowel Dis 19, 246–253 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Van den Brande, J. M. et al. Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease. Gut 56, 509–517 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Van den Brande, J. M. et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 124, 1774–1785 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Monteleone, G. et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 112, 1169–1178 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Liu, Z. et al. The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J. Leukoc. Biol. 89, 597–606 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Uhlig, H. H. et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25, 309–318 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Ahern, P. P. et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33, 279–288 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Mannon, P. J. et al. Anti-interleukin-12 antibody for active Crohn's disease. New Engl. J. Med. 351, 2069–2079 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Sandborn, W. J. et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. New Engl. J. Med. 367, 1519–1528 (2012). This large clinical trial reports the use of anti-p40 antibodies in patients with Crohn's disease who are refractory to anti-TNF therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Villarino, A. V. et al. IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD. Int. Immunol. 20, 739–752 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Cox, J. H. et al. IL-27 promotes T cell-dependent colitis through multiple mechanisms. J. Exp. Med. 208, 115–123 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Visperas, A., Do, J. S., Bulek, K., Li, X. & Min, B. IL-27, targeting antigen-presenting cells, promotes Th17 differentiation and colitis in mice. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2013.82 (2013).

  56. 56

    Hanson, M. L. et al. Oral delivery of IL-27 recombinant bacteria attenuates immune colitis in mice. Gastroenterology 146, 210–221 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Wirtz, S., Billmeier, U., McHedlidze, T., Blumberg, R. S. & Neurath, M. F. Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis. Gastroenterology 141, 1875–1886 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Troy, A. E. et al. IL-27 regulates homeostasis of the intestinal CD4+ effector T cell pool and limits intestinal inflammation in a murine model of colitis. J. Immunol. 183, 2037–2044 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Kole, A. et al. Type I IFNs regulate effector and regulatory T cell accumulation and anti-inflammatory cytokine production during T cell-mediated colitis. J. Immunol. 191, 2771–2779 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Katakura, K. et al. Toll-like receptor 9-induced type I IFN protects mice from experimental colitis. J. Clin. Invest. 115, 695–702 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Musch, E. et al. Topical treatment with the Toll-like receptor agonist DIMS0150 has potential for lasting relief of symptoms in patients with chronic active ulcerative colitis by restoring glucocorticoid sensitivity. Inflamm. Bowel Dis 19, 283–292 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010). This article highlights innate lymphoid cells as key cytokine producers in experimentally induced colitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Bernink, J. H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nature Immunol. 14, 221–229 (2013).

    Article  CAS  Google Scholar 

  65. 65

    Schulthess, J. et al. Interleukin-15-dependent NKp46+ innate lymphoid cells control intestinal inflammation by recruiting inflammatory monocytes. Immunity 37, 108–121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Fuchs, A. et al. Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-γ-producing cells. Immunity 38, 769–781 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Bishop, J. L. et al. Lyn activity protects mice from DSS colitis and regulates the production of IL-22 from innate lymphoid cells. Mucosal Immunol. 7, 405–416 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Mielke, L. A. et al. Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation. J. Exp. Med. 210, 1117–1124 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Zindl, C. L. et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc. Natl Acad. Sci. USA 110, 12768–12773 (2013).

    Article  Google Scholar 

  72. 72

    Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Eken, A., Singh, A. K., Treuting, P. M. & Oukka, M. IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol. 7, 143–154 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Fuss, I. J. et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261–1270 (1996). This is a systematic study of the differences between the cytokine profiles of Crohn's disease and ulcerative colitis.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Mudter, J. et al. The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J. Clin. Invest. 118, 2415–2426 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Weigmann, B. et al. The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J. Exp. Med. 205, 2099–2110 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Fais, S. et al. Spontaneous release of interferon-γ by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon γ inducers. Gut 32, 403–407 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Breese, E., Braegger, C. P., Corrigan, C. J., Walker-Smith, J. A. & MacDonald, T. T. Interleukin-2- and interferon-γ-secreting T cells in normal and diseased human intestinal mucosa. Immunology 78, 127–131 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Sakuraba, A. et al. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease. Gastroenterology 137, 1736–1745 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Parrello, T. et al. Up-regulation of the IL-12 receptor β 2 chain in Crohn's disease. J. Immunol. 165, 7234–7239 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Neurath, M. F. et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J. Exp. Med. 195, 1129–1143 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Szabo, S. J. et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science 295, 338–342 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Finotto, S. et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295, 336–338 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Lazarevic, V., Glimcher, L. H. & Lord, G. M. T-bet: a bridge between innate and adaptive immunity. Nature Rev. Immunol. 13, 777–789 (2013).

    Article  CAS  Google Scholar 

  85. 85

    Simpson, S. J. et al. T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon γ expression by T cells. J. Exp. Med. 187, 1225–1234 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Wirtz, S. et al. Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-γ-producing CD4+ T cells that respond to bacterial antigens. J. Immunol. 162, 1884–1888 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Fuss, I. J. & Strober, W. The role of IL-13 and NK T cells in experimental and human ulcerative colitis. Mucosal Immunol. 1 (Suppl. 1), 31–33 (2008).

    Article  CAS  Google Scholar 

  88. 88

    Heller, F. et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Heller, F., Fuss, I. J., Nieuwenhuis, E. E., Blumberg, R. S. & Strober, W. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17, 629–638 (2002).

    Article  CAS  Google Scholar 

  90. 90

    Camelo, A. et al. Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J. Gastroenterol. 47, 1198–1211 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Biancheri, P. et al. Absence of a role for interleukin-13 in inflammatory bowel disease. Eur. J. Immunol. 44, 370–385 (2013).

    Article  CAS  Google Scholar 

  92. 92

    Danese, S. et al. Tralokinumab (CAT-354), an interleukin 13 antibody, in moderate to severe ulcerative colitis: A phase 2 randomized placebo-controlled study. Presentation OP011. (European Crohn's and Colitis Organisation meeting, Copenhagen, 2014).

  93. 93

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Becker, C. et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Kobayashi, T. et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 57, 1682–1689 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Rovedatti, L. et al. Differential regulation of interleukin 17 and interferon γ production in inflammatory bowel disease. Gut 58, 1629–1636 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Sarra, M. et al. Interferon-γ-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases. Inflamm. Bowel Dis 16, 1332–1339 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Dambacher, J. et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut 58, 1207–1217 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Kamada, N. et al. 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, 568–575 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Kleinschek, M. A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Monteleone, G. et al. Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut 55, 1774–1780 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Monteleone, G. et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-γ production in Crohn's disease. Gastroenterology 128, 687–694 (2005). This article identifies IL-21 as crucial mediator of immune cell activation in Crohn's disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Siakavellas, S. I. & Bamias, G. Role of the IL-23/IL-17 axis in Crohn's disease. Discov. Med. 14, 253–262 (2012).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Leung, J. M. et al. IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue. Mucosal Immunol. 7, 124–133 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    O'Connor, W. Jr. et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nature Immunol. 10, 603–609 (2009).

    Article  CAS  Google Scholar 

  106. 106

    Leppkes, M. et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136, 257–267 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Ono, Y. et al. T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice. Gastroenterology 143, 1288–1297 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Sujino, T. et al. Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells. Gastroenterology 141, 1014–1023 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Reinisch, W. et al. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm. Bowel Dis 16, 233–242 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Powrie, F., Carlino, J., Leach, M. W., Mauze, S. & Coffman, R. L. A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 183, 2669–2674 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Huber, S. 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. Immunity 34, 554–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Davidson, N. J. et al. T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J. Exp. Med. 184, 241–251 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Marie, J. C., Liggitt, D. & Rudensky, A. Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor. Immunity 25, 441–454 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Li, M. O., Sanjabi, S. & Flavell, R. A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Maynard, C. L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3 precursor cells in the absence of interleukin 10. Nature Immunol. 8, 931–941 (2007).

    Article  CAS  Google Scholar 

  119. 119

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Monteleone, G. et al. Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. 108, 601–609 (2001). This report describes a rational strategy to target TGFβ signalling in IBD that has led to clinical trials using SMAD7 antisense DNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Fantini, M. C. et al. Smad7 controls resistance of colitogenic T cells to regulatory T cell-mediated suppression. Gastroenterology 136, 1308–1316 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Rani, R., Smulian, A. G., Greaves, D. R., Hogan, S. P. & Herbert, D. R. TGF-β limits IL-33 production and promotes the resolution of colitis through regulation of macrophage function. Eur. J. Immunol. 41, 2000–2009 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Monteleone, G. et al. Phase I clinical trial of Smad7 knockdown using antisense oligonucleotide in patients with active Crohn's disease. Mol. Ther. 20, 870–876 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Maul, J. et al. Peripheral and intestinal regulatory CD4+ CD25high T cells in inflammatory bowel disease. Gastroenterology 128, 1868–1878 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Desreumaux, P. et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology 143, 1207–1217.e2 (2012). This is the first report of the use of regulatory T cells as a therapy for Crohn's disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Pastorelli, L. et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc. Natl Acad. Sci. USA 107, 8017–8022 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Gross, P., Doser, K., Falk, W., Obermeier, F. & Hofmann, C. IL-33 attenuates development and perpetuation of chronic intestinal inflammation. Inflamm. Bowel Dis 18, 1900–1909 (2012).

    Article  Google Scholar 

  128. 128

    Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl Acad. Sci. USA 107, 18581–18586 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Sedhom, M. A. et al. Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut 62, 1714–1723 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Imaeda, H. et al. Epithelial expression of interleukin-37b in inflammatory bowel disease. Clin. Exp. Immunol. 172, 410–416 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    McNamee, E. N. et al. Interleukin 37 expression protects mice from colitis. Proc. Natl Acad. Sci. USA 108, 16711–16716 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Nava, P. et al. Interferon-γ regulates intestinal epithelial homeostasis through converging β-catenin signaling pathways. Immunity 32, 392–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Neufert, C. et al. Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK. J. Clin. Invest. 123, 1428–1443 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Bollrath, J. et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15, 91–102 (2009).

    Article  CAS  Google Scholar 

  136. 136

    Garrett, W. S. et al. Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 16, 208–219 (2009). This article links cytokines produced by innate immune cells to tumour development in intestinal inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Wang, Y. et al. Neutrophil infiltration favors colitis-associated tumorigenesis by activating the interleukin-1 (IL-1)/IL-6 axis. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2013.126 (2014).

  139. 139

    Popivanova, B. K. et al. Blocking TNF-α in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest. 118, 560–570 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Gerlach, K. et al. Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6- dependent colitis. Cancer Res. 72, 4340–4350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Stolfi, C. et al. Involvement of interleukin-21 in the regulation of colitis-associated colon cancer. J. Exp. Med. 208, 2279–2290 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Sandborn, W. J. et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. New Engl. J. Med. 367, 616–624 (2012). This is the first report of the use of a JAK multi-cytokine blocker for the treatment of IBD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Zorzi, F. et al. Distinct profiles of effector cytokines mark the different phases of Crohn's disease. PLoS ONE 8, e54562 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Verdier, J., Begue, B., Cerf-Bensussan, N. & Ruemmele, F. M. Compartmentalized expression of Th1 and Th17 cytokines in pediatric inflammatory bowel diseases. Inflamm. Bowel Dis 18, 1260–1266 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Hovhannisyan, Z., Treatman, J., Littman, D. R. & Mayer, L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 140, 957–965 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148

    Atreya, R. et al. In vivo molecular imaging using fluorescent anti-TNF antibodies predicts response to biological therapy in Crohn's disease. Nature Med. 20, 313–318 (2014). This is the first study to use molecular in vivo imaging of TNF in Crohn's disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149

    Sandborn, W. J. et al. A phase 2 study of Tofacitinib, an oral janus kinase inhibitor, in patients with Crohn's disease. Clin. Gastroenterol. Hepatol. http://dx.doi.org/10.1016/j.cgh.2014.01.029 (2014).

  150. 150

    Morrison, S. L. Two heads are better than one. Nature Biotech. 25, 1233–1234 (2007).

    Article  CAS  Google Scholar 

  151. 151

    Vandenbroucke, K. et al. Orally administered L. lactis secreting an anti-TNF Nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol. 3, 49–56 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The research of M.F.N. is supported by the Clinical Research Group (CEDER) of the German Research Council (DFG), the DFG Collaborative Research Centers 643 and 796, The German Cancer Aid organization, the United European Gastroenterology Research Prize, the DFG Graduate School of Excellence School in Advanced Optical Technologies, the Excellence program of the Friedrich-Alexander-Universität Erlangen-Nürnberg (Ludwig Demling Center), Germany, and the Interdisciplinary Center for Clinical Research (IZKF) and ELAN (Fonds für Forschung und Lehre) programmes of the University Erlangen-Nürnberg, Germany.

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Correspondence to Markus F. Neurath.

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M.F.N. has served as an adviser for MSD Pharmaceuticals, AbbVie, Pentax Corporation and Giuliani Pharma.

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Glossary

Innate lymphoid cells

(ILCs). Cells that develop from a common lymphoid progenitor but that do not express lineage markers associated with other lymphocytes. These cells rapidly secrete effector cytokines in response to activation and have been subdivided into three main groups on the basis of whether they produce T helper 1 (TH1)-, TH2- or TH17-type cytokines.

Acute-phase proteins

A group of proteins — including C-reactive protein, serum amyloid A and fibrinogen — secreted by hepatocytes into the blood in increased or decreased quantities in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Cachexia

A condition of severe weight loss, muscle wasting and debility that is caused by prolonged disease and is thought to be mediated by neuroimmunoendocrine interactions.

Necroptosis

A programmed form of necrotic cell death that is regulated by receptor-interacting protein kinase 1 (RIPK1) and RIPK3.

Nanobodies

Therapeutics that are based on the heavy-chain antibodies found in camels and llamas. Similarly to conventional antibodies, they have heavy-chain variable and constant regions but they lack light-chain domains.

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Neurath, M. Cytokines in inflammatory bowel disease. Nat Rev Immunol 14, 329–342 (2014). https://doi.org/10.1038/nri3661

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