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Differential Expression and Oxidation of MKP-1 Modulates TNF- Gene Expression

Department of Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine; and Iowa City Veterans Administration Medical Center, Iowa City, Iowa

Correspondence and requests for reprints should be addressed to A. Brent Carter, M.D., Division of Pulmonary and Critical Care Medicine, C33 GH, University of Iowa Hospital and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. E-mail: brent-carter{at}uiowa.edu

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- expression are mediated by H₂O₂ 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- production in alveolar macrophages due to insufficient H₂O₂ 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- production, respectively. In addition, TNF- 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.

Key Words: asbestosis • monocytes • hydrogen peroxide • MKP-1 • TNF-

CLINICAL RELEVANCE Asbestos is known to induce H2O2, and the release of TNF by alveolar macrophages in patients with asbestosis plays an integral role in the pathogenesis of the disease. These studies link H2O2 generation to TNF production after exposure to asbestos.

 

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