title: Macrophages survive hyperoxia via prolonged ERK activation due to phosphatase down-regulation.
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.
authors.affiliation: Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA. toru-nyunoya@uiowa.edu
authors.forename: Toru
authors.initials: T
authors.lastname: Nyunoya
authors.forename: Martha M
authors.initials: MM
authors.lastname: Monick
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.forename: Timur O
authors.initials: TO
authors.lastname: Yarovinsky
authors.forename: Gary W
authors.initials: GW
authors.lastname: Hunninghake
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D054642:Dual Specificity Phosphatase 6; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D000860:Hypoxia; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002070:Butadienes; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C113580:U 0126; D012694:Serine; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482129:Map2k2 protein, mouse; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D010744:Phosphoric Monoester Hydrolases; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D017027:Protein Tyrosine Phosphatases