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ToxSci Advance Access originally published online on May 7, 2008
Toxicological Sciences 2008 104(2):405-411; doi:10.1093/toxsci/kfn089
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Mitogen-activated Protein Kinase Kinase Kinase 1 Protects against Nickel-induced Acute Lung Injury

Maureen Mongan*,2, Zongqing Tan*,2, Liang Chen*, Zhimin Peng*, Maggie Dietsch*, Bing Su{dagger}, George Leikauf*,{ddagger} and Ying Xia*,1

* Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati, School of Medicine {dagger} Department of Immunobiology, Yale University School of Medicine {ddagger} Department of Environmental and Occupational Health, Graduate School of Public Heath, University of Pittsburgh

1 To whom correspondence should be addressed at Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, Cincinnati, OH 45267-0056. Fax: (513) 558-0974. E-mail: xiay{at}email.uc.edu.

Received March 11, 2008; accepted April 29, 2008


  Abstract

Nickel compounds are environmental and occupational hazards that pose serious health problems and are causative factors of acute lung injury. The c-jun N-terminal kinases (JNKs) are regulated through a mitogen-activated protein (MAP) 3 kinase-MAP2 kinase cascade and have been implicated in nickel toxicity. In this study, we used genetically modified cells and mice to investigate the involvement of two upstream MAP3Ks, MAP3K1 and 2, in nickel-induced JNK activation and acute lung injury. In mouse embryonic fibroblasts, levels of JNK activation and cytotoxicity induced by nickel were similar in the Map3k2-null and wild-type cells but were much lower in the Map3k1/Map3k2 double-null cells. Conversely, the levels of JNK activation and cytotoxicity were unexpectedly much higher in the Map3k1-null cells. In adult mouse tissue, MAP3K1 was widely distributed but was abundantly expressed in the bronchiole epithelium of the lung. Accordingly, MAP3K1 ablation in mice resulted in severe nickel-induced acute lung injury and reduced survival. Based on these findings, we propose a role for MAP3K1 in reducing JNK activation and protecting the mice from nickel-induced acute lung injury.

Key Words: MAP3K; MAP2K; MAPK; JNK; acute lung injury; nickel cytotoxicity.

2 These authors contributed equally to this work.


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