Interleukin-1beta, Src- and non-Src tyrosine kinases, and nitric oxide synthase induction in rat aorta in vitro.
We studied the potential roles for endogenous interleukin-1beta (IL-1beta) and for several signaling pathways in the spontaneous induction in vitro of inducible nitric oxide synthase (iNOS) in endothelium-denuded rat aorta rings. Added IL-1beta augmented, whereas the IL-1beta receptor antagonist IL-1ra blocked, spontaneous iNOS induction. Furthermore, increases in IL-1beta mRNA preceded those of iNOS mRNA. Mitogen-activated protein kinase kinase and phosphatidyl inositol 3' kinase inhibition did not block iNOS induction, whereas nuclear factor kappaB inhibition did. The sarcoma virus tyrosine kinase (Src) family-selective inhibitor 4-amino-5(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) blocked the upregulation of IL-1beta mRNA and the subsequent induction of iNOS but not the induction of iNOS stimulated by exogenously added IL-1beta. In contrast, the non-Src inhibitors TP 47/AG 213 and genistein and the tyrosine phosphatase inhibitor vanadate did not affect the spontaneous upregulation of IL-1beta mRNA but blocked both the IL-1beta-mediated and spontaneous induction of iNOS. We conclude that 1) the upregulation of tissue IL-1beta, via a signaling pathway involving a Src family kinase, plays a key role in rat vascular iNOS induction and 2) non-Src tyrosine kinases play roles downstream from IL-1beta for iNOS induction.
Endocrine Research Group, Department of Pharmacology and Therapeutics and Department of Medicine, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada T2N 4N1.
Y
Y
Gui
X L
XL
Zheng
M D
MD
Hollenberg
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002339:Carotid Arteries / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D066298:In Vitro Techniques; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic; D020032:Tyrphostins / Q000494:pharmacology; D014638:Vanadates / Q000494:pharmacology; D019061:src-Family Kinases / Q000235:genetics*
D004791:Enzyme Inhibitors; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins; D020032:Tyrphostins; C060152:tyrphostin 47; D014638:Vanadates; D019833:Genistein; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases