Cyclosporin A selectively inhibits mitogen-induced cyclooxygenase-2 gene transcription in vascular smooth muscle cells.
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.
Robida
A M
AM
Department of Pharmacology, Emory University School of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Xu
K
K
Ellington
M L
ML
Murphy
T J
TJ
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics*; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008934:Mitogens; D012333:RNA, Messenger; D016572:Cyclosporine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases