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Mol Pharmacol. 2000 Oct;58(4):701-8.

Cyclosporin A selectively inhibits mitogen-induced cyclooxygenase-2 gene transcription in vascular smooth muscle cells.

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Department of Pharmacology, Emory University School of Medicine, Emory University, Atlanta, Georgia 30322, USA.


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 Ca(2+)-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-1beta 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.

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