Map kinase phosphatase 5 protects against sepsis-induced acute lung injury.
Mitogen-activated protein kinases (MAPKs) play a critical role in inflammation. Although activation of MAPK in inflammatory cells has been studied extensively, much less is known about the inactivation of these kinases. MAPK phosphatase 5 (MKP5) is a member of the dual-specificity phosphatase family that dephosphorylates activated MAPKs. Here we report that MKP5 protects sepsis-induced acute lung injury. Mice lacking MKP5 displayed severe lung tissue damage following LPS challenge, characterized with increased neutrophil infiltration and edema compared with wild-type (WT) controls. In response to LPS, MKP5-deficient macrophages produced significantly more inflammatory factors including inflammatory cytokines, nitric oxide, and superoxide. Phosphorylation of p38 MAPK, JNK, and ERK were enhanced in MKP5-deficient macrophages upon LPS stimulation. Adoptive transfer of MKP5-deficient macrophages led to more severe lung inflammation than transfer of WT macrophages, suggesting that MKP5-deficient macrophages directly contribute to acute lung injury. Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation in inflammatory responses.
Dept. of Pharmacology, Univ. of Illinois at Chicago, Chicago, IL 60612, USA. fengqian@uic.edu
Feng
F
Qian
Jing
J
Deng
Benjamin N
BN
Gantner
Richard A
RA
Flavell
Chen
C
Dong
John W
JW
Christman
Richard D
RD
Ye
D055371:Acute Lung Injury / Q000201:enzymology* / Q000209:etiology / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D054637:Dual-Specificity Phosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D010587:Phagocytosis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D018805:Sepsis / Q000150:complications* / Q000276:immunology; D013481:Superoxides / Q000378:metabolism
D016207:Cytokines; D008070:Lipopolysaccharides; D013481:Superoxides; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; C505617:Dusp10 protein, mouse; D054637:Dual-Specificity Phosphatases