Hanyang Med Rev.  2013 Feb;33(1):27-32. 10.7599/hmr.2013.33.1.27.

Interleukin-17 in the Inflammatory Bowel Disease

• Lee CR
• Park SG

• KMID: 2168217
• DOI: http://doi.org/10.7599/hmr.2013.33.1.27

Abstract

Inflammatory bowel diseases(IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory states of the intestinal tract. While the exact mechanisms inducing chronic inflammation are still unclear, it is hypothesized that the inflammation is caused in part by an inappropriate immune response to the intestinal microflora. Although inflammatory diseases are not directly linked to patient survival, symptoms of these diseases significantly decrease quality of life. The incidence rate is higher in western people than eastern people, but the incidence rate of IBD in eastern people, including Korean, is increasing. Recently, it has been reported that IL-17 is an important factor that appears to be involved in IBD induction and progression. This report reviews many recent papers reporting the relationship between IBD and IL-17, which may provide an understanding leading to new means of prevention and treatment for IBD.

Keyword

Colitis; Interleukin-17; Th17 Cells; Receptors, Antigen, T-Cell, gamma-delta

MeSH Terms

Colitis
Colitis, Ulcerative
Crohn Disease
Humans
Incidence
Inflammation
Inflammatory Bowel Diseases
Interleukin-17
Quality of Life
Receptors, Antigen, T-Cell, gamma-delta
Th17 Cells
Interleukin-17
Receptors, Antigen, T-Cell, gamma-delta

Figure

• 

  Fig. 1 IL-17 plays an important role in intestinal infection. However, the role of IL-17 has been controversial in inflammatory bowel disease (IBD). Several groups reported that IL-17 aggravates the symptoms while other groups described improvement in the symptoms. Therefore, it needs to be clarified which factors determine the role of IL-17 in IBD for improvement and worsening of inflammation.

Reference

1. Girlich C, Scholmerich J. Topical delivery of steroids in inflammatory bowel disease. Curr Drug Deliv. 2012. 9:345–349.

2. Neuman MG, Nanau RM. Inflammatory bowel disease: role of diet, microbiota, life style. Transl Res. 2012. 160:29–44.

3. Bernstein CN, Wajda A, Svenson LW, MacKenzie A, Koehoorn M, Jackson M, et al. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol. 2006. 101:1559–1568.

4. Shin DH, Sinn DH, Kim YH, Kim JY, Chang DK, Kim EJ, et al. Increasing incidence of inflammatory bowel disease among young men in Korea between 2003 and 2008. Dig Dis Sci. 2011. 56:1154–1159.

5. Kim ES, Kim WH. Inflammatory bowel disease in Korea: epidemiological, genomic, clinical, and therapeutic characteristics. Gut Liver. 2010. 4:1–14.

6. Lee CK, Kim HJ. Pathogenesis and treatment of intestinal Behcet's disease. Korean J Gastroenterol. 2007. 50:3–8.

7. Monteleone I, Pallone F, Monteleone G. Th17-related cytokines: new players in the control of chronic intestinal inflammation. BMC Med. 2011. 9:122.

8. Morrison PJ, Ballantyne SJ, Kullberg MC. Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology. 2011. 133:397–408.

9. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011. 34:149–162.

10. McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity. 2008. 28:445–453.

11. Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. 2008. 226:57–79.

12. Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010. 10:479–489.

13. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009. 9:556–567.

14. Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003. 14:155–174.

15. Hwang SY, Kim HY. Expression of IL-17 homologs and their receptors in the synovial cells of rheumatoid arthritis patients. Mol Cells. 2005. 19:180–184.

16. Li H, Chen J, Huang A, Stinson J, Heldens S, Foster J, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci U S A. 2000. 97:773–778.

17. Yamaguchi Y, Fujio K, Shoda H, Okamoto A, Tsuno NH, Takahashi K, et al. IL-17B and IL-17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol. 2007. 179:7128–7136.

18. Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol. 2002. 169:642–646.

19. Kolls JK, Linden A. Interleukin-17 family members and inflammation. Immunity. 2004. 21:467–476.

20. 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.

21. Reynolds JM, Angkasekwinai P, Dong C. IL-17 family member cytokines: regulation and function in innate immunity. Cytokine Growth Factor Rev. 2010. 21:413–423.

22. Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH, Dong C. Cutting Edge: Regulation of Intestinal Inflammation and Barrier Function by IL-17C. J Immunol. 2012. 189:4226–4230.

23. Umemura M, Yahagi A, Hamada S, Begum MD, Watanabe H, Kawakami K, et al. IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J Immunol. 2007. 178:3786–3796.

24. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008. 28:454–467.

25. Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009. 30:108–119.

26. Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008. 14:282–289.

27. 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.

28. Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, et al. Regulation of inflammatory responses by IL-17F. J Exp Med. 2008. 205:1063–1075.

29. Kinugasa T, Sakaguchi T, Gu X, Reinecker HC. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology. 2000. 118:1001–1011.

30. Chen Y, Thai P, Zhao YH, Ho YS, DeSouza MM, Wu R. Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. J Biol Chem. 2003. 278:17036–17043.

31. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008. 29:947–957.

32. Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, 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–G838.

33. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008. 118:534–544.

34. Izcue A, Hue S, Buonocore S, Arancibia-Carcamo CV, Ahern PP, Iwakura Y, et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity. 2008. 28:559–570.

35. Noguchi D, Wakita D, Tajima M, Ashino S, Iwakura Y, Zhang Y, et al. Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a T(h)17-independent manner. Int Immunol. 2007. 19:1431–1440.

36. O'Connor W Jr, Kamanaka M, Booth CJ, Town T, Nakae S, Iwakura Y, et al. A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol. 2009. 10:603–609.

37. Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, 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.

38. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006. 116:1310–1316.

39. Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F, et al. Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology. 2008. 134:1038–1048.

40. Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C, et al. Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut. 2006. 55:1774–1780.

41. Caruso R, Fina D, Peluso I, Stolfi C, Fantini MC, Gioia V, et al. A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. Gastroenterology. 2007. 132:166–175.

42. Fantini MC, Rizzo A, Fina D, Caruso R, Becker C, Neurath MF, et al. IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells. Eur J Immunol. 2007. 37:3155–3163.

43. Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT, et al. IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol. 2007. 178:732–739.

44. Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J Immunol. 2002. 169:3600–3605.

45. Strengell M, Matikainen S, Siren J, Lehtonen A, Foster D, Julkunen I, et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol. 2003. 170:5464–5469.

46. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, 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.

47. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007. 448:484–487.

48. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007. 448:480–483.

49. Park SG, Mathur R, Long M, Hosh N, Hao L, Hayden MS, et al. T regulatory cells maintain intestinal homeostasis by suppressing gammadelta T cells. Immunity. 2010. 33:791–803.

50. Do JS, Visperas A, Dong C, Baldwin WM 3rd, Min B. Cutting edge: Generation of colitogenic Th17 CD4 T cells is enhanced by IL-17+ gamma-delta T cells. J Immunol. 2011. 186:4546–4550.