Peroxisome proliferator-activated receptor γ interacts with CIITA·RFX5 complex to repress type I collagen gene expression

Abstract

Recent reports demonstrate that peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, acts as a repressor of type I collagen synthesis. Our data demonstrate that exogenously expressed PPARγ downregulates collagen expression in a dose-responsive manner in human lung fibroblast cells. Silencing PPARγ using lentiviruses expressing short hairpin RNAs partially reverses interferon-γ (IFN-γ)-induced repression and activates collagen mRNA levels. Previous studies indicate that IFN-γ 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 PPARγ is within the RFX5·CIITA complex as judged by co-immunoprecipitation and DNA affinity precipitation studies. Most importantly, occupancy of PPARγ on the collagen transcription start site and MHC II promoter increases with IFN-γ treatment. The PPARγ agonist, troglitazone, sensitizes the cells to IFN-γ treatment by increasing recruitment of PPARγ to collagen gene while repressing collagen expression, and these effects are blocked by the PPARγ antagonist T0070907. PPARγ may mediate IFN-γ-stimulated collagen transcription down-regulation and MHC II up-regulation by interacting with CIITA as well as regulating CIITA expression. Therefore, PPARγ is a critical target for investigations into therapeutics of diseases involving extracellular matrix remodeling and the immune response. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.