Abstract
The prostaglandin synthase cyclooxygenase-2 (COX-2) is produced by an immediate early response gene induced in most cells by a variety of stimuli. Several studies have shown that the immunosuppressant cyclosporin (CsA) interferes with prostanoid metabolism, but the mechanisms are unclear. Here we examine the effect of CsA on COX-2 mRNA induction in cultured rat vascular smooth muscle cells (VSMC) that natively express the nuclear factor of activated T-cells, a known mediator of CsA-sensitive transcription. CsA significantly suppresses strong COX-2 mRNA induction caused by the Ca2+-mobilizing mitogens UTP, angiotensin II, and platelet-derived growth factor-BB, and the synergistic induction caused by costimulation with ionomycin and a phorbol ester. Forskolin and interleukin-1β are substantially weaker COX-2 mRNA inducers, and CsA does not inhibit their effect. CsA strongly inhibits UTP-, angiotensin II-, and platelet-derived growth factor-BB-stimulated COX-2 gene transcription as measured by nuclear run-on or promoter-reporter studies, but has no effect on mRNA induction caused by post-transcriptional stabilization of a distal COX-2 mRNA 3′-untranslated region regulatory element. These data show that CsA selectively inhibits mitogen-induced COX-2 gene expression by a transcriptional mechanism that may involve the nuclear factor of activated T-cells.
Footnotes
- Received March 3, 2000.
- Accepted June 21, 2000.
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Send reprint requests to: T. J. Murphy, Ph.D., Department of Pharmacology, Emory University School of Medicine, 5031 O.W. Rollins Research Bldg., Atlanta, GA 30322. E-mail:medtjm{at}bimcore.emory.edu
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Supported by Grants HL52810 and HL56107 from the National Heart Lung and Blood Institute. T.J.M. is an established investigator of the American Heart Association. A.M.R. is supported by a predoctoral training grant (GM08602-03).
- The American Society for Pharmacology and Experimental Therapeutics
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