The proinflammatory effect of prostaglandin E2 in experimental inflammatory bowel disease is mediated through the IL-23→IL-17 axis

被引:222
作者
Sheibanie, Amir F.
Yen, Jui-Hung
Khayrullina, Tanzilya
Emig, Frances
Zhang, Ming
Tuma, Ronald
Ganea, Doina
机构
[1] Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19140 USA
[2] Rutgers State Univ, Dept Biol Sci, Newark, NJ 07102 USA
关键词
D O I
10.4049/jimmunol.178.12.8138
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 PGE(2), 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 EL-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 EL-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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页码:8138 / 8147
页数:10
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