Abstract
Interleukin 23 (IL-23) and IL-17 have been linked to the pathogenesis of several chronic inflammatory disorders, including inflammatory bowel disease. Yet as an important function for IL-23 is emerging, the function of IL-17 in inflammatory bowel disease remains unclear. Here we demonstrate IL-17A-mediated protection in the CD45RBhi transfer model of colitis. An accelerated wasting disease elicited by T cells deficient in IL-17A correlated with higher expression of genes encoding T helper type 1–type cytokines in colon tissue. IL-17A also modulated T helper type 1 polarization in vitro. Furthermore, T cells deficient in the IL-17 receptor elicited an accelerated, aggressive wasting disease relative to that elicited by wild-type T cells in recipient mice. Our data demonstrate a protective function for IL-17 and identify T cells as not only the source but also a target of IL-17 in vivo.
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References
Langrish, C.L. et al. IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96–105 (2004).
Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).
Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).
Oppmann, B. et al. 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, 715–725 (2000).
Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
Honorati, M.C. et al. High in vivo expression of interleukin-17 receptor in synovial endothelial cells and chondrocytes from arthritis patients. Rheumatology (Oxford) 40, 522–527 (2001).
Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).
Schwarzenberger, P. et al. IL-17 stimulates granulopoiesis in mice: use of an alternate, novel gene therapy-derived method for in vivo evaluation of cytokines. J. Immunol. 161, 6383–6389 (1998).
Laan, M. et al. Neutrophil recruitment by human IL-17 via C–X-C chemokine release in the airways. J. Immunol. 162, 2347–2352 (1999).
Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).
Dubinsky, M.C. et al. IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease. Inflamm. Bowel Dis. 13, 511–515 (2007).
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).
Fujino, S. et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52, 65–70 (2003).
Kullberg, M.C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).
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).
Hue, S. et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J. Exp. Med. 203, 2473–2483 (2006).
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).
Ito, H. & Fathman, C.G. CD45RBhigh CD4+ T cells from IFN-γ knockout mice do not induce wasting disease. J. Autoimmun. 10, 455–459 (1997).
Zhang, Z. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm. Bowel Dis. 12, 382–388 (2006).
Ogawa, A. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).
Tlaskalová-Hogenová, H. Involvement of innate immunity in the development of inflammatory and autoimmune diseases. Ann. NY Acad. Sci. 1051, 787–798 (2005).
O'Regan, A.W., Hayden, J.M. & Berman, J.S. Osteopontin augments CD3-mediated interferon-gamma and CD40 ligand expression by T cells, which results in IL-12 production from peripheral blood mononuclear cells. J. Leukoc. Biol. 68, 495–502 (2000).
Renkl, A.C. et al. Osteopontin functionally activates dendritic cells and induces their differentiation toward a Th1-polarizing phenotype. Blood 106, 946–955 (2005).
Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103, 8137–8142 (2006).
Yang, X.O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008).
Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).
Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Harrington, L.E. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Boismenu, R., Chen, Y. & Havran, W.L. The role of intraepithelial gammadelta T cells: a gut-feeling. Microbes Infect. 1, 235–240 (1999).
Stark, M.A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).
Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).
Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).
Montgomery, R.R. et al. Recruitment of macrophages and polymorphonuclear leukocytes in Lyme carditis. Infect. Immun. 75, 613–620 (2007).
Acknowledgements
We thank G. Tokmoulina for assistance with flow cytometry cell sorting; E. Esplugues for critical reading of the manuscript and comments; A. Lin for assistance with statistical analyses; and F. Manzo for administrative assistance. Supported by the National Multiple Sclerosis Society (W.O.) and the Howard Hughes Medical Institute (R.A.F.).
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W.O. and R.A.F. designed the study and wrote the manuscript; M.K. provided flow cytometry data, advice and technical guidance; W.O. did all other in vitro and in vivo experimental work; C.J.B. did histopathological scoring analyses; T.T. provided assistance with statistical analyses; Y.I. and S.N. provided Il17a−/− mice; and J.K.K. provided the Il17ra−/− mice.
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O'Connor Jr, W., Kamanaka, M., Booth, C. et al. A protective function for interleukin 17A in T cell–mediated intestinal inflammation. Nat Immunol 10, 603–609 (2009). https://doi.org/10.1038/ni.1736
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DOI: https://doi.org/10.1038/ni.1736
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