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J. Biol. Chem., Vol. 279, Issue 43, 44695-44703, October 22, 2004

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Oxidants Inhibit ERK/MAPK and Prevent Its Ability to Delay Neutrophil Apoptosis Downstream of Mitochondrial Changes and at the Level of XIAP^*

Shyra J. Gardai, Ben B. Whitlock¶, Yi Qun Xiao, Donna B. Bratton, and Peter M. Henson||

From the Program in Cell Biology, the Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, the Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262, and the ^¶Department of Biology, West Virginia Wesleyan College, Buckhannon, West Virginia 26201

Normal spontaneous apoptosis in neutrophils is enhanced by "stress" stimuli such as tumor necrosis factor-, Fas ligand, and oxidants, and this effect is inhibited by anti-apoptotic stimuli including granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, and formylmethionine-leucine-phenylalanine. In this report we demonstrate that anti-apoptotic stimuli protect neutrophils from stress-induced apoptosis via activation of the ERK/MAPK pathway. The protection occurs downstream of mitochondrial alterations assessed as a decrease in membrane potential concomitant with enhanced cytochrome c release. ERK activation was shown to inhibit apoptosis by maintaining levels of XIAP, which is normally decreased in the presence of the pro-apoptotic/stress stimuli. This report also demonstrates that potent intra- and extracellular oxidants inhibit the protective effect of ERK. Oxidant-dependent inhibition of ERK was because of activation of p38 MAPK and activation of the protein phosphatases PP1 and PP2A. Our data suggest that ERK suppresses stress-induced apoptosis downstream of mitochondrial alterations by maintaining XIAP levels and that oxidants block this effect through activation of p38 and protein phosphatases.

Received for publication, May 12, 2004 , and in revised form, July 29, 2004.

^* 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: National Jewish Medical and Research Center, D508, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1380; Fax: 303-398-1381; E-mail: hensonp{at}NJC.org.

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