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J. Biol. Chem., Vol. 282, Issue 36, 26046-26056, September 7, 2007

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Peroxisome Proliferator-activated Receptor Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression^*

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Recent reports demonstrate that peroxisome proliferator-activated receptor (PPAR), a member of the nuclear receptor superfamily, acts as a repressor of type I collagen synthesis. Our data demonstrate that exogenously expressed PPAR down-regulates collagen expression in a dose-responsive manner in human lung fibroblast cells. Silencing PPAR using lentiviruses expressing short hairpin RNAs partially reverses interferon- (IFN-)-induced repression and activates collagen mRNA levels. Previous studies indicate that IFN- represses collagen gene expression and induces major histocompatibility complex II (MHC II) expression by activating the formation of a regulatory factor for X-box 5 (RFX5) complex with class II transactivator (CIITA). This report demonstrates that PPAR is within the RFX5·CIITA complex as judged by co-immunoprecipitation and DNA affinity precipitation studies. Most importantly, occupancy of PPAR on the collagen transcription start site and MHC II promoter increases with IFN- treatment. The PPAR agonist, troglitazone, sensitizes the cells to IFN- treatment by increasing recruitment of PPAR to collagen gene while repressing collagen expression, and these effects are blocked by the PPAR antagonist T0070907. PPAR may mediate IFN--stimulated collagen transcription down-regulation and MHC II up-regulation by interacting with CIITA as well as regulating CIITA expression. Therefore, PPAR is a critical target for investigations into therapeutics of diseases involving extracellular matrix remodeling and the immune response.

Received for publication, May 2, 2007 , and in revised form, June 28, 2007.

^* This work was supported by National Institutes of Health (NIH) Public Health Services Grants HL68094 and HL013262–31 (to B. D. S.), by NHLBI, NIH Grants DK51586 and DK58825 (to S. R. F.), by the NIDDK, NIH, and by American Heart Association post-doctoral fellowship Grant 0525981T (to Y. X.). 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 Biochemistry, Boston University School of Medicine, 715 Albany St., Boston, MA 02118. Tel.: 617-638-4159; Fax: 617-638-5339; E-mail: smith{at}biochem.bumc.bu.edu.

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