Peroxisome proliferator-activated receptor-gamma activation inhibits interleukin-1 beta-mediated platelet-derived growth factor-alpha receptor gene expression via CCAAT/enhancer-binding protein-delta 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 demons trated that the interaction between C/EBPs and PPARs plays a central role i n 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 prolifera tion activity of VSMCs, Electromobility shift and supershift assays for a C /EBP motif in the PDGF alphaR promoter region revealed that PPAR gamma acti vators suppressed IL-1 beta -induced DNA binding activity of C/EBP delta an d beta. PPAR gamma activators also suppressed IL-1 beta -induced C/EBP delt a expression. In contrast, overexpression of C/EBP delta reversed the suppr essive effect of PPAR gamma activators on PDGF alphaR expression almost com pletely. From these results, we conclude that the inhibitory effect of PPAR gamma activators on PDGF alphaR expression is mainly mediated by C/EBP del ta suppression. Regulation of C/EBP delta by PPAR gamma activators probably plays critical roles in modulating inflammatory responses in the arterial wall.