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J. Biol. Chem., Vol. 279, Issue 3, 2020-2029, January 16, 2004

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Phosphorylation of Tumor Necrosis Factor Receptor 1 (p55) Protects Macrophages from Silica-induced Apoptosis^*

Federica Gambelli, Peter Di, Xiaomei Niu, Mitchell Friedman, Timothy Hammond¶, David W. H. Riches||, and Luis A. Ortiz**

From the Division of Occupational Medicine, Department of Environmental and Occupational Health at the University of Pittsburgh, Pittsburgh, Pennsylvania 15261, The sections of Pulmonary, Critical Care and Environmental Medicine and ^¶Nephrology, Department of Medicine at Tulane Health Sciences Center, New Orleans, Louisiana 70112, and the ^||Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206

Macrophages play a fundamental role in silicosis in part by removing silica particles and producing inflammatory mediators in response to silica. Tumor necrosis factor (TNF) is a prominent mediator in silicosis. Silica induction of apoptosis in macrophages might be mediated by TNF. However, TNF also activates signal transduction pathways (NF-B and AP-1) that rescue cells from apoptosis. Therefore, we studied the TNF-mediated mechanisms that confer macrophage protection against the pro-apoptotic effects of silica. We will show that exposure to silica induced TNF production by RAW 264.7 cells, but not by IC-21. Silica-induced activation of NF-B and AP-1 was only observed in RAW 264.7 macrophages. ERK activation in response to silica exposure was only observed in RAW 264.7 macrophages, whereas activation of p38 phosphorylation was predominantly observed in IC-21 macrophages. No changes in JNK activity were observed in either cell line in response to silica exposure. Silica induced apoptosis in both macrophage cell lines, but the induction of apoptosis was significantly larger in IC-21 cells. Protection against apoptosis in RAW 264.7 cells in response to silica was mediated by enhanced NF-B activation and ERK-mediated phosphorylation of the p55 TNF receptor. Inhibition of these two protective mechanisms by specific pharmacological inhibitors or transfection of dominant negative mutants that inhibit IB or ERK phosphorylation significantly increased silica-induced apoptosis in RAW 264.7 macrophages. These data suggest that NF-B activation and ERK-mediated phosphorylation of the p55 TNF receptor are important cell survival mechanisms in the macrophage response to silica exposure.

Received for publication, September 3, 2003

^* This work was supported by United States Public Health Service Grant ES10859-01A1 (to L. A. O.), by Grant ES08663 (to M. F.) from NIEHS, National Institutes of Health (NIH), by Grants HL55549, HL65326, and HL68628 (to D. W. H. R.) from NHLBI, NIH, and by a grant from the Wetmore Foundation (to F. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Environmental and Occupational Health, Division of Occupational and Environmental Medicine, Graduate School of Public Health, the University of Pittsburgh, A731 Crabtree Hall, 130 De Soto St., Pittsburgh, PA 15261. Tel.: 412-624-3155; Fax: 412-624-3040; e-mail: lao1{at}pitt.edu.

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