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

Tomotake Tokunou, Toshihiro Ichiki, Kotaro Takeda, Yuko Funakoshi, Naoko Iino, Hiroaki Shimokawa, Kensuke Egashira, Akira Takeshita

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)


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-induced IL-6 expression in VSMCs. Thrombin induced IL-6 mRNA and protein expression in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK), or epidermal growth factor receptor (EGF-R) suppressed the thrombin-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 bp 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. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced IL-6 mRNA expression. These results suggest that the CRE site and CREB play an important role in thrombin-induced IL-6 gene expression in VSMCs. Transactivation of EGF-R and activation of ERK and p38 MAPK are involved in this process. CREB may be a novel transcription factor that regulates thrombin-induced gene expression.

Original languageEnglish
Pages (from-to)1759-1763
Number of pages5
JournalArteriosclerosis, thrombosis, and vascular biology
Issue number11
Publication statusPublished - 2001

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine


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