PPARγ enhances IFNγ-mediated transcription and rescues the TGFβ antagonism by stimulating CIITA in vascular smooth muscle cells

Chronic inflammatory response and active vascular remodeling are two featured pathophysiological events during atherogenesis. Gamma interferon (IFN-γ) modulates these two processes through transcriptional control of major histocompatibility complex II (MHC II) and collagen type I (COL1A2) genes, mediated by class II transactivator (CIITA). Transforming growth factor (TGF-β) antagonizes the effect of IFN-γ in part by dampening the expression of CIITA. Here we report that peroxisome proliferator activated receptor γ (PPARγ) enhanced MHC II activation and COL1A2 repression by IFN-γ while rescuing the antagonism by TGF-β in a CIITA-dependent manner in human aortic smooth muscle cells judged by quantitative PCR and luciferase reporter assays. PPARγ exerted its effect by augmenting the levels of CIITA and stimulating CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays. The up-regulation of CIITA levels was the result of PPARγ-mediated transcriptional activation of CIITA through promoter IV, and increased CIITA protein stability. Thus, our data suggest that PPARγ could be a key factor in fine-tuning inflammation as well as restructuring of vessel walls during atherogenesis by acting as a “balance tipper” of the differential effects exerted by cytokines.