期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 281, 期 25, 页码 16985-16990出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M602446200
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Glycogen synthase kinase-3 beta(GSK-3 beta) is a serine/threonine kinase with a broad array of cellular targets, such as cytoskeletal proteins and transcription factors. Recent studies with GSK-3 beta-null mice showed impaired NF kappa B-mediated survival responses. Because NF kappa B serves a dual role as a key regulator of cytokine-induced inflammatory gene expression and apoptosis, we investigated whether modulation of GSK-3 beta expression affects cytokine-induced and NF kappa B-mediated inflammatory gene expression. We observed that tumor necrosis factor-alpha( TNF-alpha) and interleukin-1 beta(IL-1 beta) treatment of primary cultures of human microvascular cells reduced net endogenous active GSK-3 beta protein levels while inducing inflammatory cytokine(IL-6 and monocyte chemoattractant protein-1 (MCP-1)) expression. Interestingly, inhibition of GSK-3 beta by antisense oligonucleotides or pharmacological agent ( 10 mM lithium) potentiated TNF-induced expression of IL-6 and MCP-1 by 2-6-fold suggesting that inhibition of GSK-3 beta under inflammatory conditions ( exposure to TNF-alpha and IL-1 beta) may contribute to enhanced cytokine expression. Overexpression of GSK-3 beta in endothelial cells, in contrast, significantly inhibited ( by 70%, p < 0.01) both TNF-alpha and IL-1 beta-induced expression of IL-6, MCP-1, and vascular cell adhesion molecule-1. Using adenoviruses in lipopolysaccharide-stimulated mice, overexpression of GSK-3 beta significantly decreased TNF-alpha expression in lung and heart tissues ( 38 and 15%, respectively), further confirming the anti-inflammatory role of GSK-3 beta. Overexpression of GSK-3 beta did not affect the TNF-alpha-induced nuclear translocation of NF kappa B but reduced the nuclear half-life of TNF-alpha-induced NF kappa B considerably ( by as much as 9 h) and enhanced phosphorylation ( by as much as 33%). Interestingly, neither endothelial cell survival nor NF kappa B-mediated expression of anti-apoptotic genes was affected by GSK-3 beta overexpression. We conclude that GSK-3 beta selectively regulates NF kappa B-mediated inflammatory gene expression by controlling the flow of NF kappa B activity between transcription of inflammatory and survival genes.
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