Abstract
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.
Highlights
Depend on the balanced control of matrix remodeling and inflammation
We have demonstrated that interferon-␥ (IFN-␥), an important inflammatory cytokine, represses collagen transcription, in part, through the induction of regulatory factor for X box 5 (RFX5) complex proteins and Class II transactivator (CIITA), and their recruitment to the collagen transcription start site [22,23,24]
We demonstrate that PPAR␥ is recruited to a complex with RFX5 and CIITA at the collagen transcription start site and the major histocompatibility complex II (MHC II) promoter during IFN-␥ treatment
Summary
PPAR␥, peroxisome proliferator-activated receptor ␥; CIITA, class II transactivator; RFX, regulatory factor for X-box; IFN-␥, interferon-␥; Trog, troglitazone; COL1A1, collagen ␣1 type I gene; COL1A2, collagen ␣2 type I gene; MHC II, major histocompatibility complex type II; TGF-, transforming growth factor-; NF-1, nuclear factor-1; GFP, green fluorescent protein. PPAR␥ Interacts with RFX51⁄7CIITA Complex immune response through transcriptional activation of major histocompatibility complex II (MHC II). We demonstrate that PPAR␥ is recruited to a complex with RFX5 and CIITA at the collagen transcription start site and the MHC II promoter during IFN-␥ treatment. The IFN-␥-induced repression of collagen and activation of MHC II transcription is enhanced in the presence of PPAR␥ agonists and reversed by PPAR␥ antagonists. Silencing PPAR␥ blocks the IFN-␥induced collagen repression
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