Peroxisome proliferator-activated receptor gamma interacts with CIITA x RFX5 complex to repress type I collagen gene expression.
Recent reports demonstrate that peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, acts as a repressor of type I collagen synthesis. Our data demonstrate that exogenously expressed PPARgamma down-regulates collagen expression in a dose-responsive manner in human lung fibroblast cells. Silencing PPARgamma using lentiviruses expressing short hairpin RNAs partially reverses interferon-gamma (IFN-gamma)-induced repression and activates collagen mRNA levels. Previous studies indicate that IFN-gamma 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 PPARgamma is within the RFX5.CIITA complex as judged by co-immunoprecipitation and DNA affinity precipitation studies. Most importantly, occupancy of PPARgamma on the collagen transcription start site and MHC II promoter increases with IFN-gamma treatment. The PPARgamma agonist, troglitazone, sensitizes the cells to IFN-gamma treatment by increasing recruitment of PPARgamma to collagen gene while repressing collagen expression, and these effects are blocked by the PPARgamma antagonist T0070907. PPARgamma may mediate IFN-gamma-stimulated collagen transcription down-regulation and MHC II up-regulation by interacting with CIITA as well as regulating CIITA expression. Therefore, PPARgamma is a critical target for investigations into therapeutics of diseases involving extracellular matrix remodeling and the immune response.
Xu
Yong
Y
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Farmer
Stephen R
SR
Smith
Barbara D
BD
D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D024042:Collagen Type I / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020868:Gene Silencing; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016086:Lentivirus; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000077288:Troglitazone; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001549:Benzamides; D002839:Chromans; D024042:Collagen Type I; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D047495:PPAR gamma; D011725:Pyridines; C093524:RFX5 protein, human; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; C458508:T 0070907; D045162:Thiazolidinediones; D015534:Trans-Activators; D007371:Interferon-gamma; D000077288:Troglitazone