NF-kappaB is required for TNF-alpha-directed smooth muscle cell migration.
Migration of vascular smooth muscle cells (VSMC) is a crucial event in the formation of vascular stenotic lesions. Tumor necrosis factor-alpha (TNF-alpha) is elaborated by VSMC in atherosclerosis and following angioplasty. We investigated the role of nuclear factor-kappaB (NF-kappaB) in human VSMC migration induced by TNF-alpha. Adenoviral expression of a mutant form of the inhibitor of NF-kappaB, IkappaB-alphaM, suppressed TNF-alpha-triggered degradation of cellular IkappaB-alpha, inhibited activation of NF-kappaB, and attenuated TNF-alpha-induced migration. Further, IkappaB-alphaM suppressed TNF-alpha-stimulated release of interleukin-6 and -8 (IL-6 and IL-8). Neutralization of IL-6 and IL-8 with appropriate antibodies reduced TNF-alpha-induced VSMC migration. Addition of recombinant IL-6 and IL-8 stimulated migration. Collectively, our data provide initial evidence that TNF-alpha-mediated VSMC migration requires NF-kappaB activation and is associated with induction of IL-6 and IL-8 which act in an autocrine manner.
Wang
Z
Z
Division of Basic Medical Science, Mercer University School of Medicine, Macon, GA 31207, USA. wang_z@mercer.edu
Castresana
M R
MR
Newman
W H
WH
D000256:Adenoviridae / Q000235:genetics; D019898:Autocrine Communication; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005822:Genetic Vectors; D006801:Humans; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D003609:Dactinomycin; D003513:Cycloheximide