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Oxidants Selectively Reverse TGF- Suppression of Proinflammatory Mediator Production¹

Yi Qun Xiao^*, Celio G. Freire-de-Lima, William J. Janssen^*, Konosuke Morimoto^*, Dennis Lyu^*, Donna L. Bratton^* and Peter M. Henson^2,*

^* Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206; and Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Although TGF- 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- 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-B-driven production of proinflammatory mediators, which were inhibited by TGF-. 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-. This was mediated through Src tyrosine kinases and protein phosphatase-1/2A. By contrast, hydrogen peroxide had no effects on TGF--induced Smad2 phosphorylation and SBE-luc reporter gene transcription.

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