Evidence that G alpha(q)-coupled receptor-induced interleukin-6 mRNA in vascular smooth muscle cells involves the nuclear factor of activated T cells

The immunosuppressant cyclosporin A inhibits transcription mediated by the nuclear factor of activated T-cells (NFAT), a key regulator of cytokine gen e expression in lymphocytes that integrates phospholipase C signaling. NFAT is also expressed in vascular smooth muscle cells, but the genes it regula tes there are unknown. Here we show that G alpha(q)-coupled P2Y nucleotide receptor signaling in rat vascular smooth muscle cells increases NFAT-media ted luciferase reporter expression. It also induces interleukin (IL)-6 gene expression but not other cytokine mRNAs including IL-1, IL-2, IL-3, IL-4, IL-10, gamma-interferon, tumor necrosis factor-alpha, or tumor necrosis fac tor-beta. IL-6 mRNA induction by UTP is more rapid and transient then that caused by IL-1 beta stimulation and is partially blocked by cyclosporin A o r by expression of a trans-dominant NFAT inhibitor. Expression of recombina nt NFATc1 markedly augments IL-6 mRNA induction by these and other agonists , which is partially attributable to NFAT-regulated paracrine mediators. Ho wever, trans-dominant NF kappa B inhibitors strongly interfere with IL-6 mR NA induction both by IL-1 beta and by UTP, which synergistically evoke IL-6 mRNA expression. These findings suggest that NFAT is among the cofactors i nvolved in NF kappa B-dependent IL-6 gene induction by Ca2+-mobilizing rece ptors in vascular smooth muscle cells.