title: Mitogen-activated protein kinase phosphatase 2 regulates the inflammatory response in sepsis.
abstract: Sepsis results from a dysregulation of the regulatory mechanisms of the pro- and anti-inflammatory response to invading pathogens. The mitogen-activated protein (MAP) kinase cascades are key signal transduction pathways involved in the cellular production of cytokines. The dual-specific phosphatase 1 (DUSP 1), mitogen-activated protein kinase phosphatase-1 (MKP-1), has been shown to be an important negative regulator of the inflammatory response by regulating the p38 and Jun N-terminal protein kinase (JNK) MAP kinase pathways to influence pro- and anti-inflammatory cytokine production. MKP-2, also a dual-specific phosphatase (DUSP 4), is a phosphatase highly homologous with MKP-1 and is known to regulate MAP kinase signaling; however, its role in regulating the inflammatory response is not known. We hypothesized a regulatory role for MKP-2 in the setting of sepsis. Mice lacking the MKP-2 gene had a survival advantage over wild-type mice when challenged with intraperitoneal lipopolysaccharide (LPS) or a polymicrobial infection via cecal ligation and puncture. The MKP-2(-/-) mice also exhibited decreased serum levels of both pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin-1beta [IL-1beta], IL-6) and anti-inflammatory cytokines (IL-10) following endotoxin challenge. Isolated bone marrow-derived macrophages (BMDMs) from MKP-2(-/-) mice showed increased phosphorylation of the extracellular signal-regulated kinase (ERK), decreased phosphorylation of JNK and p38, and increased induction of MKP-1 following LPS stimulation. The capacity for cytokine production increased in MKP-2(-/-) BMDMs following MKP-1 knockdown. These data support a mechanism by which MKP-2 targets ERK deactivation, thereby decreasing MKP-1 and thus removing the negative inhibition of MKP-1 on cytokine production.
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan School of Medicine, and CS Mott Children's Hospital, Ann Arbor, Michigan 48109-0243, USA. ttcornel@med.umich.edu
authors.forename: Timothy T
authors.initials: TT
authors.lastname: Cornell
authors.forename: Paul
authors.initials: P
authors.lastname: Rodenhouse
authors.forename: Qing
authors.initials: Q
authors.lastname: Cai
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Shanley
mesh_terms: D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D016207:Cytokines / Q000097:blood; D054638:Dual Specificity Phosphatase 1 / Q000032:analysis; D005260:Female; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity; D048670:MAP Kinase Kinase 4 / Q000032:analysis; D008264:Macrophages / Q000737:chemistry / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010538:Peritonitis / Q000276:immunology; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*; D016019:Survival Analysis; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases