title: Oxidants selectively reverse TGF-beta suppression of proinflammatory mediator production.
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.
authors.affiliation: Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Yi Qun
authors.initials: YQ
authors.lastname: Xiao
authors.forename: Celio G
authors.initials: CG
authors.lastname: Freire-de-Lima
authors.forename: William J
authors.initials: WJ
authors.lastname: Janssen
authors.forename: Konosuke
authors.initials: K
authors.lastname: Morimoto
authors.forename: Dennis
authors.initials: D
authors.lastname: Lyu
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D007952:Leukemia, Plasma Cell; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016877:Oxidants; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases