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J. Biol. Chem., Vol. 283, Issue 21, 14182-14189, May 23, 2008

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Impaired Bcl3 Up-regulation Leads to Enhanced Lipopolysaccharide-induced Interleukin (IL)-23P19 Gene Expression in IL-10^–/– Mice^*

Marcus Mühlbauer, Paula M. Chilton, Thomas C. Mitchell, and Christian Jobin¹

From the Department of Medicine, Pharmacology and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 and the Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky 40202

Genetic and biochemical analyses show that IL-23p19 plays a central role in mediating bacteria-induced colitis in interleukin-10-deficient (IL-10^–/–) mice. The molecular mechanisms responsible for the dysregulated innate host response leading to enhanced IL-23 gene expression in IL-10^–/– mice are poorly understood. In this study, we investigated the role of Bcl3 in controlling LPS-induced IL-23p19 gene expression in bone marrow-derived dendritic cells (BMDC) isolated from IL-10^–/– mice. We report higher IL-23p19 mRNA accumulation and protein secretion in LPS-stimulated BMDC isolated from IL-10^–/– compared with WT mice. Lipopolysaccharide (LPS)-induced B cell leukemia 3 (Bcl3) expression was strongly impaired (90% decrease) in IL-10^–/– BMDC compared with WT BMDC. Chromatin immunoprecipitation demonstrated enhanced RelA binding to the IL-23p19 promoter in IL-10^–/– compared with WT BMDC. Bcl3 overexpression decreased LPS-induced IL-23p19 gene expression in IL-10^–/– BMDC, which correlated with enhanced NF-B p50 binding and decreased RelA binding to the gene promoter. Conversely, Bcl3 knockdown enhanced LPS-induced IL-23p19 gene expression in WT BMDC. Moreover, LPS-induced IL-23p19 gene expression was significantly enhanced in Bcl3^–/– BMDC compared with WT BMDC. In conclusion, enhanced LPS-induced IL-23p19 gene expression in IL-10^–/– mice is due to impaired Bcl3 expression leading to diminished p50 and enhanced RelA recruitment to the IL-23p19 promoter.

Received for publication, November 2, 2007 , and in revised form, March 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants ROI DK 47700 and RO1 DK 73338 (to C. J.). This work was also supported by Deutsche Forschungsgemeinschaft Grant MU2301/2-1 (to M. M.). 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 To whom correspondence should be addressed: Dept. of Medicine, Pharmacology, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-966-7884; Fax: 919-966-7468; E-mail: job{at}med.unc.edu.

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