Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells

The plasma level of interleukin-6 (IL-6) is elevated in patients with acute coronary syndromes and has prognostic value. Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. We examined the mechanism of thrombin-indu ced IL-6 expression in VSMCs. Thrombin induced IL-6 mRNA and protein expres sion in a dose-dependent manner. Pharmacological inhibition of extracellula r signal-regulated protein kinase (ERK), p38 mitogen-activated protein kina se (MAPK), or epidermal growth factor receptor (EGF-R) suppressed the throm bin-induced IL-6 expression. Deletion and mutation analysis of the promoter region of the IL-6 gene by using luciferase as a reporter showed that the DNA segment between -228 and -150 by containing the cAMP response element ( CRE) site played a critical role. Thrombin also induced phosphorylation of CRE binding protein (CREB) in an ERK- and a p38 MAPK-dependent manner. Over expression of the dominant-negative form of CREB inhibited thrombin-induced IL-6 mRNA expression. These results suggest that the CRE site and CREB pla y an important role in thrombin-induced IL-6 gene expression in VSMCs. Tran sactivation of EGF-R and activation of ERK and p38 MAPK are involved in thi s process. CREB may be a novel transcription factor that regulates thrombin -induced gene expression.