Peroxisome proliferator-activated receptor-γ activation inhibits interleukin-1β-mediated platelet-derived growth factor-α receptor gene expression via CCAAT/enhancer-binding protein-δ in vascular smooth muscle cells

CCAAT/enhancer-binding protein (C/EBP)-binding motifs have been identified in the promoter regions of interleukin (IL)-6, tumor necrosis factor-alpha, and platelet-derived growth factor-alpha receptor (PDGF alphaR), Recently, peroxisome proliferator-activated receptors (PPARs) have been suggested to be important immunomodulatory mediators. Although many studies have demonstrated that the interaction between C/EBPs and PPARs plays a central role in lipid metabolism, expression and function of these factors are unknown in vascular smooth muscle cells (VSMCs), In the present study, we clarified a functional relationship between C/EBPs and PPAR gamma in the regulation of IL-1 beta -induced PDGF alphaR expression in VSMCs, PPAR gamma activators, troglitazone and 15-deoxy-Delta (12,14)-prostaglandin J(2), inhibited IL-1 beta -induced PDGF alphaR expression and suppressed PDGF-induced proliferation activity of VSMCs, Electromobility shift and supershift assays for a C/EBP motif in the PDGF alphaR promoter region revealed that PPAR gamma activators suppressed IL-1 beta -induced DNA binding activity of C/EBP delta and beta. PPAR gamma activators also suppressed IL-1 beta -induced C/EBP delta expression. In contrast, overexpression of C/EBP delta reversed the suppressive effect of PPAR gamma activators on PDGF alphaR expression almost completely. From these results, we conclude that the inhibitory effect of PPAR gamma activators on PDGF alphaR expression is mainly mediated by C/EBP delta suppression. Regulation of C/EBP delta by PPAR gamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.