Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury.
Acute lung injury (ALI) is mediated by an early proinflammatory response resulting from either a direct or indirect insult to the lung mediating neutrophil infiltration and consequent disruption of the alveolar capillary membrane ultimately leading to refractory hypoxemia. The mitogen-activated protein kinase (MAPK) pathways are a key component of the molecular response activated by those insults triggering the proinflammatory response in ALI. The MAPK pathways are counterbalanced by a set of dual-specific phosphatases (DUSP) that deactivate the kinases by removing phosphate groups from tyrosine or threonine residues. We have previously shown that one DUSP, MKP-2, regulates the MAPK pathway in a model of sepsis-induced inflammation; however, the role of MKP-2 in modulating the inflammatory response in ALI has not been previously investigated. We utilized both MKP-2-null (MKP-2(-/-)) mice and MKP-2 knockdown in a murine macrophage cell line to elucidate the role of MKP-2 in regulating inflammation during ALI. Our data demonstrated attenuated proinflammatory cytokine production as well as decreased neutrophil infiltration in the lungs of MKP-2(-/-) mice following direct, intratracheal LPS. Importantly, when challenged with a viable pathogen, this decrease in neutrophil infiltration did not impact the ability of MKP-2(-/-) mice to clear either gram-positive or gram-negative bacteria. Furthermore, MKP-2 knockdown led to an attenuated proinflammatory response and was associated with an increase in phosphorylation of ERK and induction of a related DUSP, MKP-1. These data suggest that altering MKP-2 activity may have therapeutic potential to reduce lung inflammation in ALI without impacting pathogen clearance.
Division of Pediatric Critical Care Medicine, Dept. of Pediatrics and Communicable Diseases, Univ. of Michigan Medical School, C S Mott Children's Hospital, Ann Arbor, MI 48109-0243, USA. ttcornel@med.umich.edu
Timothy T
TT
Cornell
Andrew
A
Fleszar
Walker
W
McHugh
Neal B
NB
Blatt
Ann Marie
AM
Le Vine
Thomas P
TP
Shanley
D055371:Acute Lung Injury / Q000150:complications* / Q000276:immunology* / Q000382:microbiology; D000818:Animals; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000472:pathogenicity
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases