Persistent activation of nuclear factor-kappaB by interleukin-1beta and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase.
The role of extracellular signal-regulated kinase (ERK) was studied in the signaling pathway by which interleukin-1beta (IL-1beta) increases the expression of inducible NO synthase (iNOS) in rat vascular smooth muscle cells. IL-1beta induced a rapid and transient activation of nuclear factor-kappaB (NF-kappaB), followed by a prolonged activation of NF-kappaB that was required to induce iNOS expression. Either PD98059 or U0126, selective inhibitors of ERK activation, did not influence IL-1beta-induced early activation but effectively reduced the prolonged activation of NF-kappaB and significantly reduced IL-1beta induction of iNOS. Transfection with antisense, but not sense, phosphorothioate-modified oligodeoxynucleotides directed toward ERK also reduced IL-1beta-induced prolonged NF-kappaB activation and iNOS expression. IkappaBbeta, but not IkappaBalpha degradation, induced by IL-1beta was markedly attenuated when ERK activation was inhibited and could be partially responsible for the persistent NF-kappaB activation. These data suggest that ERK activity is required for persistent NF-kappaB activation by IL-1beta that is necessary for iNOS gene expression.
Jiang
B
B
Whitaker Cardiovascular Institute, Vascular Biology Unit, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. bjiang@bu.edu
Brecher
P
P
Cohen
R A
RA
D000818:Animals; D001013:Aorta, Thoracic; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D014158:Transcription, Genetic
D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007375:Interleukin-1; D016328:NF-kappa B; D009570:Nitriles; C113580:U 0126; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one