Differential expression and oxidation of MKP-1 modulates TNF-alpha gene expression.
Monocytic cells are integral in the pathogenesis of inflammatory disorders. We have shown previously that asbestos-induced p38 mitogen-activated protein (MAP) kinase activation and TNF-alpha expression are mediated by H(2)O(2) in blood monocytes. Due to the high expression and activity of catalase and glutathione peroxidase, normal alveolar macrophages do not respond in a manner similar to that of blood monocytes. Since kinase activity is tightly regulated by phosphatases, we hypothesized that the dual specificity phosphatase MAP kinase phosphatase (MKP)-1 regulates p38 activity and TNF-alpha production in alveolar macrophages due to insufficient H(2)O(2) generation in response to asbestos. We found that MKP-1 was highly expressed in alveolar macrophages, while blood monocytes had minimal expression. Inhibition of expression and activity of MKP-1 or overexpression of a catalytic mutant MKP-1 recovered p38 activity in alveolar macrophages. We questioned whether MKP-1 oxidation played a role dictating the contrasting responses of these cells to asbestos exposure, and found that overexpressed wild-type MKP-1 in monocytes was oxidized, while the mutant MKP-1 remained in the reduced form. Monocytes overexpressing either catalase or wild-type MKP-1 had decreased p38 activation and TNF-alpha production, respectively. In addition, TNF-alpha gene expression was regained in alveolar macrophages overexpressing the catalytic mutant MKP-1. These data suggest that MKP-1, through increased expression and lack of oxidation, modulates the inflammatory response in alveolar macrophages exposed to asbestos.
Tephly
Linda A
LA
Department of Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
Carter
A Brent
AB
D000293:Adolescent; D000328:Adult; D017638:Asbestos, Crocidolite / Q000633:toxicity; D001483:Base Sequence; D002374:Catalase / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017931:DNA Primers; D014409:Tumor Necrosis Factor-alpha; D017638:Asbestos, Crocidolite; D002374:Catalase; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1