Mitogen-activated protein kinase kinase kinase 1 protects against nickel-induced acute lung injury.
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.
Mongan
Maureen
M
Department of Environmental Health and Center of Environmental Genetics, University of Cincinnati, School of Medicine, Cincinnati, OH 45267-0056, USA.
Tan
Zongqing
Z
Chen
Liang
L
Peng
Zhimin
Z
Dietsch
Maggie
M
Su
Bing
B
Leikauf
George
G
Xia
Ying
Y
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D007509:Irritants / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009532:Nickel / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D007509:Irritants; C029938:nickel sulfate; D009532:Nickel; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048670:MAP Kinase Kinase 4