Differential regulation of vascular smooth muscle nuclear factor kappa-B by G alpha q-coupled and cytokine receptors.
NF kappaB has been implicated as a downstream effector of G alphaq-coupled receptor signaling, but whether these and cytokine receptors activate NF kappaB similarly remains unclear. Stimulation of rat vascular smooth muscle cell G alphaq-coupled P2Y nucleotide receptors with UTP induces luciferase transcription from a sensitive and specific NF kappaB dependent promoter. However, these responses are only;15% of that to the reference cytokine IL-1 beta. IL-1 beta is a powerful stimulator of I kappaB alpha degradation, RelA nuclear import, and isoform specific NF kappaB enhancer binding in vitro, responses that are not detectable after P2Y receptor stimulation. Expression of two trans -dominant NF kappaB polypeptides suppresses induction of the NF kappaB reporter and also IL-1 beta 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 beta, implying that G alphaq-coupled receptor evokes additional NF kappaB-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 beta treatment. NF kappaB is less efficiently activated then several other transcriptional effectors of G alphaq-coupled receptor signaling in vascular smooth muscle cells, and is instead preferentially activated by inflammatory cytokines.
Abbott
K L
KL
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Robida
A M
AM
Davis
M E
ME
Pavlath
G K
GK
Camden
J M
JM
Turner
J T
JT
Murphy
T J
TJ
D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism; D014544:Uridine Triphosphate / Q000378:metabolism / Q000494:pharmacology
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C546385:P2RY2 protein, human; C546386:P2ry2 protein, mouse; C546387:P2ry2 protein, rat; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; C497593:RELB protein, human; D017472:Receptors, Interleukin-1; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C497594:Relb protein, mouse; C497595:Relb protein, rat; D051996:Transcription Factor RelA; D014157:Transcription Factors; C099845:purinoceptor P2Y6; D051841:Transcription Factor RelB; D000077214:Becaplermin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D014544:Uridine Triphosphate