Temporal control of NF-kappaB activation by ERK differentially regulates interleukin-1beta-induced gene expression.
In cultured rat vascular smooth muscle cells, sustained activation of ERK is required for interleukin-1beta to persistently activate NF-kappaB. Without ERK activation, interleukin-1beta induces only acute and transient NF-kappaB activation. The present study examined whether the temporal control of NF-kappaB activation by ERK could differentially regulate the expression of NF-kappaB-dependent genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1), and manganese-containing superoxide dismutase (Mn-SOD). Treatment of vascular smooth muscle cells with interleukin-1beta induced the expression of iNOS, COX-2, VCAM-1, and Mn-SOD in a time-dependent manner, but with different patterns. Either PD98059 or U0126, selective inhibitors of MEK, or overexpression of a dominant negative MEK-1 inhibited interleukin-1beta- induced ERK activation and the expression of iNOS and COX-2 but had essentially no effect on the expression of VCAM-1 and Mn-SOD. The expression of these genes was inhibited when NF-kappaB activation was down-regulated by MG132, a proteasome inhibitor, or by overexpression of an I-kappaBalpha mutant that prevented both the transient and the persistent activation of NF-kappaB. Inhibition of ERK did not affect interleukin-1beta-induced I-kappaBalpha phosphorylation and degradation but attenuated I-kappaBbeta degradation. Thus, although NF-kappaB activation was essential for interleukin-1beta induction of each of the proteins studied, gene expression was differentially regulated by ERK and by the duration of NF-kappaB activation. These results reveal a novel functional role for ERK as an important temporal regulator of NF-kappaB activation and NF-kappaB-dependent gene expression.
Jiang
Bingbing
B
Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA. bjiang@bu.edu
Xu
Shanqin
S
Hou
Xiuyun
X
Pimentel
David R
DR
Brecher
Peter
P
Cohen
Richard A
RA
D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D002070:Butadienes; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; D019010:Vascular Cell Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D020928:Mitogen-Activated Protein Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one