Transcriptional regulation of the platelet-derived growth factor α receptor gene via CCAAT/enhancer-binding protein-δ in vascular smooth muscle cells

Inflammatory cytokines stimulate the proliferation of vascular smooth muscle cells (VSMC) and play a pivotal role in the pathogenesis of vascular diseases including atherosclerosis and restenosis. Mitogenic response of interleukin-1 beta (IL-1 beta) on VSMC is thought to be mediated by induction of endogenous platelet-derived growth factor (PDGF), especially PDGF-AA. Although the action of PDGF-AA is mediated by its specific receptor, PDGF alpha-receptor (PDGF alpha R), very little is known about the regulatory mechanism of PDGF alpha R gene expression in VSMC. To understand the mechanism, we studied the transcriptional control of the PDGF alpha R gene in VSMC after treatment with IL-1 beta, IL-1 beta (10 ng/ml) drastically increased both PDGF alpha R and CCAAT/enhancer-binding protein delta (C/EBP delta) mRNA levels in a time dependent manner. A rapid induction of C/EBP delta mRNA within 30 min was followed by slower emergence of PDGF alpha R mRNA, which reached the maximum level in 12 h, whereas C/EBP delta mRNA was detectable at 30 min and reached the maximum level at 3 h, Electromobility shift and supershift assays revealed that IL-1 beta markedly increased DNA-protein complex, which was mainly composed of C/EBP beta and/or -delta. Both Western blotting and immunohistochemistry demonstrated that either C/EBP beta or -delta expression was induced by IL-1 beta exclusively in nuclei of VSMC, On the other hand, overexpression of C/EBP delta specifically transactivated the promoter activity of the PDGF alpha R gene and significantly enhanced VSMC proliferation in PDGF-treated cells. We conclude that induction of PDGF alpha R expression is mainly mediated by C/EBP delta expression in VSMC, and a high level of C/EBP delta expression may be involved in the pathogenesis of atherosclerosis and restenosis.