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The IL-23/IL-17 Axis in Inflammation

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The IL-23/IL-17 Axis in Inflammation The IL-23/IL-17 axis in inflammation Yoichiro Iwakura, Harumichi Ishigame J Clin Invest. 2006;116(5):1218-1222. https://doi.org/10.1172/JCI28508. Commentary + IL-23 induces the differentiation of naive CD4 T cells into highly pathogenic helper T cells (Th17/ThIL-17) that produce IL- 17, IL-17F, IL-6, and TNF-α, but not IFN-γ and IL-4. Two studies in this issue of the JCI demonstrate that blocking IL-23 or its downstream factors IL-17 and IL-6, but not the IL-12/IFN-γ pathways, can significantly suppress disease development in animal models of inflammatory bowel disease and MS (see the related articles beginning on pages 1310 and 1317). These studies suggest that the IL-23/IL-17 pathway may be a novel therapeutic target for the treatment of chronic inflammatory diseases. Find the latest version: https://jci.me/28508/pdf commentaries mediated by complement bypass systems. trigger these more ancient bypass pathways. 6. Knutzen-Steuer, K.L., et al. 1989. Lysis of sensitized sheep erythrocytes in human sera deficient in the Fourth, and probably most important, the Using our current methods, such pathways second component of complement. J. Immunol. type of assay represents the wave of the are not analyzed in clinical medicine or in 143:2256–2261. future in detecting the activity of the com- animal models of human disease. 7. Selander, B., et al. 2006. Mannan-binding lectin plement system in human disease. As these activates C3 and the alternative complement pathway without involvement of C2. J. Clin. Invest. more informative detection systems (like the Address correspondence to: John P. Atkin- 116:1425–1434. doi:10.1172/JCI25982. one used in this report) come into routine son, Washington University School of Med- 8. Seelen, M.A., et al. 2005. Functional analysis of the clinical use, other examples of these bypass icine, 660 South Euclid Avenue, Box 8045, classical, alternative, and MBL pathways of the com- plement system: standardization and validation of type pathways will likely be uncovered. For St. Louis, Missouri 63110, USA. Phone: a simple ELISA. J. Immunol. Methods. 296:187–198. human diseases, these more specific and (314) 362-8391; Fax: (314) 362-1366; 9. Deguchi, M., Gillin, F.D., and Gigli, I. 1987. Mecha- quantitative assay systems will establish E-mail: [email protected]. nism of killing of Giardia lamblia trophozoites by which pathway of complement activation is complement. J. Clin. Invest. 79:1296–1302. 10. Wagner, E., Platt, J.L., Howell, D.N., Marsh, H.C., playing a role in disease and elucidate which 1. May, J.E., and Frank, M.M. 1973. A new comple- ment-mediated cytolytic mechanism-the C1-bypass Jr., and Frank, M.M. 1999. IgG and complement- one to modulate with therapeutic agents. activation pathway. Proc. Natl. Acad. Sci. U. S. A. mediated tissue damage in the absence of C2: evi- Finally, a word of caution is in order. These 70:649–652. dence of a functionally active C2-bypass pathway in bypass pathways are often not considered 2. May, J.E., and Frank, M.M. 1973. Hemolysis of sheep a guinea pig model. J. Immunol. 163:3549–3558. erythrocytes in guinea pig serum deficient in the 11. Traustadottir, K.H., Rafnar, B.O., Steinsson, K., by investigators attempting to define the fourth component of complement. I. Antibody and Valdimarsson, H., and Erlendsson, K. 1998. Par- role of the complement system in disease serum requirements. J. Immunol. 111:1661–1667. ticipation of factor B in residual immune complex states. For example, C4-deficient animals 3. May, J.E., and Frank, M.M. 1973. Hemolysis of sheep red cell binding activity observed in serum from a erythrocytes in guinea pig serum deficient in the C2-deficient systemic lupus erythematosus patient are widely used to rule out a contribution of fourth component of complement. II. Evidence for may delay the appearance of clinical symptoms. the classical pathway and/or lectin pathway involvement of C1 and components of the alternate Arthritis Rheum. 41:427–434. in mouse models of human disease. One complement pathway. J. Immunol. 111:1668–1676. 12. Klint, C., Gullstrand, B., Sturfelt, G., and Truedsson, must be wary of such interpretations in 4. Matsushita, M., and Okada, H. 1986. Alternative L. 2000. Binding of immune complexes to erythro- complement pathway activation by C4b deposited cyte CR1 (CD35): difference in requirement of clas- view of bypass cascades that become opera- during classical pathway activation. J. Immunol. sical pathway components and indication of alter- tive in “deficient” states. Thus the natural 136:2994–2998. native pathway-mediated binding in C2-deficiency. maturation of an antibody response to an 5. Farries, T.C., Knutzen Steuer, K.L., and Atkinson, Scand. J. Immunol. 52:103–108. J.P. 1990. The mechanism of activation of the alter- 13. Nolin, L., et al. 1979. Possible C1q bypass loop acti- infectious organism (i.e., to go rapidly into native pathway of complement by cell-bound C4b. vation in the haemolytic uraemic syndrome. Clin. antibody excess) is all that is necessary to Mol. Immunol. 27:1155–1161. Exp. Immunol. 35:107–111. The IL-23/IL-17 axis in inflammation Yoichiro Iwakura and Harumichi Ishigame Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan. IL-23 induces the differentiation of naive CD4+ T cells into highly pathogen- STAT6 activation, promoting the expres- ic helper T cells (Th17/ThIL-17) that produce IL-17, IL-17F, IL-6, and TNF-α, sion of GATA-3, a transcriptional factor but not IFN-γ and IL-4. Two studies in this issue of the JCI demonstrate that essential for both IL-4 production and Th2 blocking IL-23 or its downstream factors IL-17 and IL-6, but not the IL-12/ cell differentiation. Recently, it was report- IFN-γ pathways, can significantly suppress disease development in animal ed that CD4+ T cells isolated from the models of inflammatory bowel disease and MS (see the related articles begin- inflamed joints of patients with Lyme dis- ning on pages 1310 and 1317). These studies suggest that the IL-23/IL-17 ease contain a subset of IL-17–producing pathway may be a novel therapeutic target for the treatment of chronic CD4+ T cells that are distinct from those inflammatory diseases. producing either IL-4 or IFN-γ (Figure 1) + (1). These IL-17–producing CD4 T cells + Th17/ThIL-17 is a new CD4 helper functions (Figure 1). Th1 cells produce were dubbed Th17 or ThIL-17 cells (2–4). T cell subset that produces IL-17 large quantities of IFN-γ and mediate cel- IL-17, a proinflammatory cytokine pre- Upon antigenic stimulation, naive CD4+ lular immunity while Th2 cells, which are dominantly produced by activated T cells, T cells differentiate into 2 subsets, Th1 involved in humoral immunity, primar- enhances T cell priming and stimulates and Th2 cells, characterized by different ily produce IL-4, IL-5, and IL-13. IL-12, a fibroblasts, endothelial cells, macrophages, cytokine production profiles and effector heterodimer of the p40 and p35 subunits, and epithelial cells to produce multiple pro- induces the differentiation of naive CD4+ inflammatory mediators, including IL-1, Nonstandard abbreviations used: CIA, collagen- T cells into IFN-γ–producing Th1 cells IL-6, TNF-α, NOS-2, metalloprote- induced arthritis; IBD, inflammatory bowel disease; through activation of STAT4. IFN-γ signals ases, and chemokines, resulting in the IL-1Ra, IL-1 receptor antagonist; R, receptor. are transduced by STAT1, which activates induction of inflammation (5, 6). IL-17 Conflict of interest: The authors have declared that no conflict of interest exists. a downstream transcription factor, T-bet, expression is increased in patients with Citation for this article: J. Clin. Invest. 116:1218–1222 that enhances the expression of genes spe- a variety of allergic and autoimmune (2006). doi:10.1172/JCI28508. cific to Th1 cells. In contrast, IL-4 induces diseases, such as RA, MS, inflamma- 1218 The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 5 May 2006 commentaries to demonstrate that IL-23, but not IL-12, is essential for the development of intestinal inflammation (15). They used IL-10–/– mice as a model of T cell–mediated IBD (16) and showed that the development of colitis was greatly suppressed by IL-23p19 deficiency but not IL-12p35 deficiency. Exogenous IL-23 administration accelerated the onset of colitis in Rag–/– mice engrafted with IL-10–/–CD4+ T cells. Notably, IL-17 pro- duction was abolished in IL-23p19–/– mice while IFN-γ and IL-4 production were unaf- fected. IL-17 and IL-6 expression by anti- CD3 mAb–stimulated memory CD4+ T cells were augmented by IL-23, but not by IL-12, indicating that IL-23 can simulate memory CD4+ T cells. This result contrasts with the ability of IL-12 to stimulate naive CD4+ T cells. Moreover, treatment with both anti– IL-6 and anti–IL-17 mAbs significantly ame- Figure 1 liorated the severity of the intestinal inflam- + –/– IL-23 promotes the development of an IL-17–producing CD4 helper T cell subset. IL-23 induc- mation induced by IL-23–treated Rag mice + es the differentiation of naive CD4 T cells into IL-17–producing helper T cells (Th17/ThIL-17) via engrafted with IL-10–/–CD4+CD45RBhi T mechanisms that are distinct from the Th1 and Th2 differentiation pathways. The transcriptional cells. These observations suggest that IL-17 factors critical for the development of Th1 (STAT1, STAT4, and T-bet) and Th2 (STAT6) cells and IL-6 derived from memory T cells are are not required for the induction of Th17/Th cells.
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