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 immed iate early response gene induced in most cells by a variety of stimuli. Sev eral studies have shown that the immunosuppressant cyclosporin (CsA) interf eres with prostanoid metabolism, but the mechanisms are unclear. Here we ex amine the effect of CsA on COX-2 mRNA induction in cultured rat vascular sm ooth muscle cells (VSMC) that natively express the nuclear factor of activa ted T-cells, a known mediator of CsA-sensitive transcription. CsA significa ntly suppresses strong COX-2 mRNA induction caused by the Ca2+ mobilizing m itogens 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-1 beta are substantially weaker COX-2 mRN A inducers, and CsA does not inhibit their effect. CsA strongly inhibits UT P-, angiotensin II-, and platelet-derived growth factor-BB-stimulated COX-2 gene transcription as measured by nuclear run-on or promoter-reporter stud ies, but has no effect on mRNA induction caused by post-transcriptional sta bilization of a distal COX-2 mRNA 3'-untranslated region regulatory element . These data show that CsA selectively inhibits mitogen-nduced COX-2 gene e xpression by a transcriptional mechanism that may involve the nuclear facto r of activated T-cells.