PT  - JOURNAL ARTICLE
AU  - Aaron M. Robida
AU  - Kaiming Xu
AU  - Michelle L. Ellington
AU  - T. J. Murphy
TI  - Cyclosporin A Selectively Inhibits Mitogen-Induced Cyclooxygenase-2 Gene Transcription in Vascular Smooth Muscle Cells
AID  - 10.1124/mol.58.4.701
DP  - 2000 Oct 01
TA  - Molecular Pharmacology
PG  - 701--708
VI  - 58
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/58/4/701.short
4100  - http://molpharm.aspetjournals.org/content/58/4/701.full
SO  - Mol Pharmacol2000 Oct 01; 58
AB  - 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.