Evidence that Galpha(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 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 Galpha(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, gamma-interferon, tumor necrosis factor-alpha, or tumor necrosis factor-beta. IL-6 mRNA induction by UTP is more rapid and transient then that caused by IL-1beta stimulation and is partially blocked by cyclosporin A or by expression of a trans-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 NFkappaB inhibitors strongly interfere with IL-6 mRNA induction both by IL-1beta and by UTP, which synergistically evoke IL-6 mRNA expression. These findings suggest that NFAT is among the cofactors involved in NFkappaB-dependent IL-6 gene induction by Ca(2+)-mobilizing receptors in vascular smooth muscle cells.
Abbott
K L
KL
Department of Pharmacology and Graduate Program in Molecular and Systems Pharmacology, Emory University School of Medicine, Atlanta, Georgia, USA.
Loss
J R
JR
Robida
A M
AM
Murphy
T J
TJ
D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008213:Lymphocyte Activation; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019899:Paracrine Communication / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058472:Receptors, Purinergic P2Y1; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation; D014544:Uridine Triphosphate / Q000378:metabolism
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; C546384:P2ry1 protein, rat; D012333:RNA, Messenger; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D014157:Transcription Factors; D016572:Cyclosporine; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D014544:Uridine Triphosphate