TY - JOUR T1 - Cyclosporin A Selectively Inhibits Mitogen-Induced Cyclooxygenase-2 Gene Transcription in Vascular Smooth Muscle Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 701 LP - 708 DO - 10.1124/mol.58.4.701 VL - 58 IS - 4 AU - Aaron M. Robida AU - Kaiming Xu AU - Michelle L. Ellington AU - T. J. Murphy Y1 - 2000/10/01 UR - http://molpharm.aspetjournals.org/content/58/4/701.abstract N2 - 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. ER -