Linked Life Data

20351138

Source:http://linkedlifedata.com/resource/pubmed/id/20351138

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2010-5-20
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1098-5522
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
78
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2868-76
pubmed:dateRevised
2011-3-3
pubmed:meshHeading
pubmed-meshheading:20351138-Animals, pubmed-meshheading:20351138-Bacterial Infections, pubmed-meshheading:20351138-Cytokines, pubmed-meshheading:20351138-Dual Specificity Phosphatase 1, pubmed-meshheading:20351138-Female, pubmed-meshheading:20351138-Inflammation, pubmed-meshheading:20351138-Lipopolysaccharides, pubmed-meshheading:20351138-MAP Kinase Kinase 4, pubmed-meshheading:20351138-Macrophages, pubmed-meshheading:20351138-Male, pubmed-meshheading:20351138-Mice, pubmed-meshheading:20351138-Mice, Inbred C57BL, pubmed-meshheading:20351138-Mice, Knockout, pubmed-meshheading:20351138-Peritonitis, pubmed-meshheading:20351138-Protein Tyrosine Phosphatases, pubmed-meshheading:20351138-Sepsis, pubmed-meshheading:20351138-Survival Analysis, pubmed-meshheading:20351138-p38 Mitogen-Activated Protein Kinases
pubmed:year
2010
pubmed:articleTitle
Mitogen-activated protein kinase phosphatase 2 regulates the inflammatory response in sepsis.
pubmed: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
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural