Abstract
Although TGF-beta inhibits the production of proinflammatory mediators in vitro and in vivo, its anti-inflammatory activities may be ineffective in early or severe acute inflammatory circumstances. In this study, we suggest a role for oxidative stress on TGF-beta signaling, leading to prevention of its normal anti-inflammatory effects but leaving its Smad-driven effects on cellular differentiation or matrix production unaffected. Stimulation of the RAW 264.7 macrophage cells, human or mouse alveolar macrophages with LPS led to NF-kappaB-driven production of proinflammatory mediators, which were inhibited by TGF-beta. This inhibition was prevented in the presence of hydrogen peroxide. We found that hydrogen peroxide acted by inducing p38 MAPK activation, which then prevented the ERK activation and MAPK phosphatase-1 up-regulation normally induced by TGF-beta. This was mediated through Src tyrosine kinases and protein phosphatase-1/2A. By contrast, hydrogen peroxide had no effects on TGF-beta-induced Smad2 phosphorylation and SBE-luc reporter gene transcription.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / metabolism
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Dual Specificity Phosphatase 1
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Genes, Reporter / drug effects
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Humans
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Immediate-Early Proteins / metabolism
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In Vitro Techniques
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Inflammation Mediators / metabolism*
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Leukemia, Plasma Cell
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Lipopolysaccharides / toxicity
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MAP Kinase Signaling System / drug effects
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Macrophages / drug effects*
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Macrophages / immunology*
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Macrophages / metabolism
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Macrophages, Alveolar / drug effects
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Macrophages, Alveolar / immunology
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Macrophages, Alveolar / metabolism
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Mice
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Models, Biological
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NF-kappa B / metabolism
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Nitric Oxide Synthase Type II / biosynthesis
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Oxidants / pharmacology*
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Oxidative Stress
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Phosphoprotein Phosphatases / metabolism
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Protein Phosphatase 1
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Protein Tyrosine Phosphatases / metabolism
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Signal Transduction / drug effects
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Smad2 Protein / metabolism
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Transcription, Genetic / drug effects
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Transforming Growth Factor beta / metabolism*
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Up-Regulation / drug effects
Substances
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Cell Cycle Proteins
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Immediate-Early Proteins
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Inflammation Mediators
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Lipopolysaccharides
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NF-kappa B
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Oxidants
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Smad2 Protein
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Smad2 protein, mouse
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Transforming Growth Factor beta
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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DUSP1 protein, human
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse
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Protein Tyrosine Phosphatases