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J. Biol. Chem., Vol. 280, Issue 28, 26295-26302, July 15, 2005

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Macrophages Survive Hyperoxia via Prolonged ERK Activation Due to Phosphatase Down-regulation^*

Toru Nyunoya, Martha M. Monick¶, Linda S. Powers, Timur O. Yarovinsky, and Gary W. Hunninghake¶

From the Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242 and ^¶Veterans Affairs Medical Center, Department of Veterans Affairs, Iowa City, Iowa 52246

Macrophages exposed to hyperoxia in the lung continue to survive for prolonged periods. We previously reported (Nyunoya, T., Powers, L. S., Yarovinsky, T. O., Butler, N. S., Monick, M. M., and Hunninghake, G. W. (2003) J. Biol. Chem. 278, 36099–36106) that hyperoxia induces cell cycle arrest and sustained extracellular signal-related kinase (ERK) activity in macrophages. In this study, we determined the mechanisms of hyperoxia-induced ERK activation and how ERK activity plays a pro-survival role in hyperoxia-exposed cells. Inhibition of ERK activity decreased survival of hyperoxia-exposed macrophages. This was due, at least in part, to down-regulation of the pro-apoptotic Bcl-2 family member, BimEL. In determining the mechanism of ERK activation by hyperoxia, we found that ERK activation was not associated with hyperoxia-induced activation of the upstream ERK kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2. When we examined the ability of whole cell lysates from hyperoxia-exposed cells to dephosphorylate purified phosphorylated ERK, we found decreased ERK-directed phosphatase activity. Two particular ERK-directed phosphatases (protein phosphatase 2A and MAPK phosphatase-3) demonstrated decreased activity in hyperoxia-exposed cells. Moreover, whole cell lysates from normoxia-exposed cells depleted of PP2A or MAPK phosphatase-3 were also less able to dephosphorylate ERK. These data demonstrate that, in hyperoxia-exposed macrophages, sustained activation of ERK due to phosphatase down-regulation permits macrophage survival via effects on the balance between pro- and anti-apoptotic Bcl-2 family proteins.

Received for publication, January 6, 2005 , and in revised form, May 17, 2005.

^* This work was supported by a Veterans Affairs merit review grant, National Institutes of Health Grants HL-60316 and HL-077431, General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health Grant RR00059, and American Lung Association Grant RT-806-N. 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: Division of Pulmonary, Critical Care, and Occupational Medicine, 100 EMRB, Iowa City, IA 52242. Tel.: 319-335-7590; Fax: 319-335-6530; E-mail: toru-nyunoya{at}uiowa.edu.

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