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Differential Regulation of Chemokines by IL-17 in Colonic Epithelial Cells¹

Jimmy W. Lee^*, Ping Wang^*, Michael G. Kattah, Sawsan Youssef, Lawrence Steinman^,, Kathryn DeFea^2,* and Daniel S. Straus^2,*

^* Biomedical Sciences Division, University of California, Riverside, CA 92521; and Program in Immunology and Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305

The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF--stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF- for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF- in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Senior Investigator Award from the Crohn’s and Colitis Foundation of America (to D.S.S.) and National Institutes of Health Grants R01-GM066151 (to K.D.) and R01-NS55997 (to L.S.).

² Address correspondence and reprint requests to Dr. Daniel S. Straus or Dr. Kathryn DeFea, Biomedical Sciences Division, University of California, Riverside, CA 92521-0121. E-mail addresses: straus{at}ucr.edu and katie.defea{at}ucr.edu

³ Abbreviations used in this paper: DRB, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole; DAPI, 4,6-diamidino-2-phenylindole; EGFR, epidermal growth factor receptor; ISRE, IFN stimulatory response element.

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