Differential Regulation of Vascular Smooth Muscle Nuclear Factor kappa-B by G α q-coupled and Cytokine Receptors

Abstract

NF κB has been implicated as a downstream effector of G αq-coupled receptor signaling, but whether these and cytokine receptors activate NF κB similarly remains unclear. Stimulation of rat vascular smooth muscle cell G αq-coupled P2Y nucleotide receptors with UTP induces luciferase transcription from a sensitive and specific NF κB dependent promoter. However, these responses are only 15% of that to the reference cytokine IL-1 β. IL-1 β is a powerful stimulator of I κB α degradation, RelA nuclear import, and isoform specific NF κB enhancer binding in vitro, responses that are not detectable after P2Y receptor stimulation. Expression of two trans -dominant NF κB polypeptides suppresses induction of the NF κB reporter and also IL-1 β stimulated monocyte chemoattractant-1 mRNA, which is not induced by UTP. In contrast, UTP induces higher expression of the endogenous COX-2 and IL-6 mRNAs than does IL-1 β, implying that G αq-coupled receptor evokes additional NF κB-independent transcription factors in regulating these two genes. P2Y receptors are as effective as the reference growth factor PDGF-BB at inducing CREB, AP-1, SRE and NFAT transcription, which are largely unaffected by IL-1 β treatment. NF κB is less efficiently activated then several other transcriptional effectors of G αq-coupled receptor signaling in vascular smooth muscle cells, and is instead preferentially activated by inflammatory cytokines.