Abstract

The immunosuppressant cyclosporin A inhibits transcription mediated by the nuclear factor of activated T-cells (NFAT), a key regulator of cytokine gene expression in lymphocytes that integrates phospholipase C signaling. NFAT is also expressed in vascular smooth muscle cells, but the genes it regulates there are unknown. Here we show that Gα_q-coupled P2Y nucleotide receptor signaling in rat vascular smooth muscle cells increases NFAT-mediated 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, γ-interferon, tumor necrosis factor-α, or tumor necrosis factor-β. IL-6 mRNA induction by UTP is more rapid and transient then that caused by IL-1β stimulation and is partially blocked by cyclosporin A or by expression of atrans-dominant NFAT inhibitor. Expression of recombinant NFATc1 markedly augments IL-6 mRNA induction by these and other agonists, which is partially attributable to NFAT-regulated paracrine mediators. However, trans-dominant NFκB inhibitors strongly interfere with IL-6 mRNA induction both by IL-1β and by UTP, which synergistically evoke IL-6 mRNA expression. These findings suggest that NFAT is among the cofactors involved in NFκB-dependent IL-6 gene induction by Ca²⁺-mobilizing receptors in vascular smooth muscle cells.