Macrophages survive hyperoxia via prolonged ERK activation due to phosphatase down-regulation

Toru Nyunoya; Martha M Monick; Linda S Powers; Timur O Yarovinsky; Gary W Hunninghake

doi:10.1074/jbc.M500185200

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Macrophages survive hyperoxia via prolonged ERK activation due to phosphatase down-regulation

Journal article

Open access

Peer reviewed

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

The Journal of biological chemistry, Vol.280(28), pp.26295-26302

07/15/2005

DOI: 10.1074/jbc.M500185200

PMID: 15901735

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Abstract

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.

Adaptor Proteins, Signal Transducing - metabolism

Animals

Apoptosis Regulatory Proteins

Bcl-2-Like Protein 11

Blotting, Western

Butadienes - pharmacology

Cell Survival

Cells, Cultured

Down-Regulation

Dual Specificity Phosphatase 6

Enzyme Activation

Enzyme Inhibitors - pharmacology

Extracellular Signal-Regulated MAP Kinases - metabolism

Hypoxia

Macrophages - metabolism

Macrophages - pathology

MAP Kinase Kinase 1 - metabolism

MAP Kinase Kinase 2 - metabolism

MAP Kinase Signaling System

Membrane Proteins

Mice

Mitogen-Activated Protein Kinase 1 - metabolism

Mitogen-Activated Protein Kinase 3 - metabolism

Models, Biological

Nitriles - pharmacology

Phosphoprotein Phosphatases - metabolism

Phosphoric Monoester Hydrolases - metabolism

Phosphorylation

Protein Phosphatase 2

Protein Tyrosine Phosphatases - metabolism

Proto-Oncogene Proteins

Proto-Oncogene Proteins c-bcl-2 - metabolism

Recombinant Proteins - chemistry

Serine - chemistry

Time Factors

Details

Title: Subtitle: Macrophages survive hyperoxia via prolonged ERK activation due to phosphatase down-regulation
Creators: Toru Nyunoya - University of Iowa
Martha M Monick - University of Iowa
Linda S Powers - University of Iowa
Timur O Yarovinsky - University of Iowa
Gary W Hunninghake - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(28), pp.26295-26302
DOI: 10.1074/jbc.M500185200
PMID: 15901735
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: HL-60316 / NHLBI NIH HHS RR00059 / NCRR NIH HHS HL-077431 / NHLBI NIH HHS
Language: English
Date published: 07/15/2005
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984622051402771

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