Abstract
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-1beta (IL-1beta) 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, PDGFalpha-receptor (PDGFalphaR), very little is known about the regulatory mechanism of PDGFalphaR gene expression in VSMC. To understand the mechanism, we studied the transcriptional control of the PDGFalphaR gene in VSMC after treatment with IL-1beta. IL-1beta (10 ng/ml) drastically increased both PDGFalphaR and CCAAT/enhancer-binding protein delta (C/EBPdelta) mRNA levels in a time dependent manner. A rapid induction of C/EBPdelta mRNA within 30 min was followed by slower emergence of PDGFalphaR mRNA, which reached the maximum level in 12 h, whereas C/EBPdelta mRNA was detectable at 30 min and reached the maximum level at 3 h. Electromobility shift and supershift assays revealed that IL-1beta markedly increased DNA-protein complex, which was mainly composed of C/EBPbeta and/or -delta. Both Western blotting and immunohistochemistry demonstrated that either C/EBPbeta or -delta expression was induced by IL-1beta exclusively in nuclei of VSMC. On the other hand, overexpression of C/EBPdelta specifically transactivated the promoter activity of the PDGFalphaR gene and significantly enhanced VSMC proliferation in PDGF-treated cells. We conclude that induction of PDGFalphaR expression is mainly mediated by C/EBPdelta expression in VSMC, and a high level of C/EBPdelta expression may be involved in the pathogenesis of atherosclerosis and restenosis.
Highlights
In a number of vascular diseases including atherosclerosis, hypertension, and restenosis that often occurs after balloon angioplasty [1,2,3]
Messenger RNA Induction of platelet-derived growth factor (PDGF)␣R and C/EBP␦ by IL1—vascular smooth muscle cells (VSMC) derived from Harlan Sprague-Dawley rats were incubated for 6 h in the presence of IL-1 at various concentrations (0 – 40 ng/ml), and mRNA levels of both PDGF ␣-receptor (PDGF␣R) and C/EBP␦ were determined by Northern blotting
Previous studies revealed that C/EBP␦ expression was usually at an undetectable or minor level in normal cells or tissues and was rapidly induced by lipopolysaccharide and inflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor ␣ (28 –30)
Summary
In a number of vascular diseases including atherosclerosis, hypertension, and restenosis that often occurs after balloon angioplasty [1,2,3]. We have investigated the molecular mechanism of PDGF␣R gene transcription in VSMC and obtained results indicating that IL-1 induces PDGF␣R gene expression via a trans-acting nuclear factor, CCAAT/enhancer-binding protein ␦ (C/EBP␦).
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