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IL-17 Axis1
* Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140; and
Department of Biological Sciences, Rutgers University, Newark, NJ 07102
Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23
IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.
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1 This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant RO1AI052306.
2 Address correspondence and reprint requests to Dr. Doina Ganea, Department of Physiology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. E-mail address: doina.ganea{at}temple.edu
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; CrD, Crohn’s disease; UC, ulcerative colitis; TNBS, 2,4,6-trinitrobenzene sulfonic acid; DC, dendritic cell; rm, recombinant murine; MPO, myeloperoxidase; MLN, mesenteric lymph node; MPO, myeloperoxidase; LPDC, lamina propria DC; Cox, cyclooxygenase.
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