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Essential Roles of c-Rel in TLR-Induced IL-23 p19 Gene Expression in Dendritic Cells¹

Ruaidhrí J. Carmody^*, Qingguo Ruan^*, Hsiou-Chi Liou and Youhai H. Chen^2,*

^* Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Department of Medicine, Cornell University Medical College, New York, NY 10021

IL-23 plays crucial roles in both immunity against pathogens and autoimmunity against self. Although it is well recognized that IL-23 expression is restricted to the myeloid lineage and is tightly regulated at the transcriptional level, the nature of transcription factors required for IL-23 expression is poorly understood. We report, in this study, that murine dendritic cells deficient in c-Rel, a member of the NF-B family, are severely compromised in their ability to transcribe the p19 gene, one of the two genes that encode the IL-23 protein. The p19 gene promoter contains three putative NF-B binding sites, two of which can effectively bind c-Rel as determined by chromatin immunoprecipitation and EMSA. Unexpectedly, mutation of either of these two c-Rel binding sites completely abolished the p19 promoter activity induced by five TLRs (2, 3, 4, 6, and 9) and four members of the NF-B family (c-Rel, p65, p100, and p105). Based on these observations, we conclude that c-Rel controls IL-23 p19 gene expression through two B sites in the p19 promoter, and propose a c-Rel-dependent enhanceosome model for p19 gene activation.

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 National Institutes of Health Grants AI50059, AI055934, and AI55934.

² Address correspondence and reprint requests to Dr. Youhai H. Chen, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, 614 Biomedical Research Building II/III, Philadelphia, PA 19104. E-mail address: yhc{at}mail.med.upenn.edu

³ Abbreviations used in this paper: DC, dendritic cell; ChIP, chromatin immunoprecipitation; IRF, IFN regulatory factor; PGN, peptidoglycan; WT, wild type; F, forward; R, reverse.

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