PMID- 20351138
OWN - NLM
STAT- MEDLINE
DCOM- 20100601
LR  - 20220318
IS  - 1098-5522 (Electronic)
IS  - 0019-9567 (Print)
IS  - 0019-9567 (Linking)
VI  - 78
IP  - 6
DP  - 2010 Jun
TI  - Mitogen-activated protein kinase phosphatase 2 regulates the inflammatory 
      response in sepsis.
PG  - 2868-76
LID - 10.1128/IAI.00018-10 [doi]
AB  - 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.
FAU - Cornell, Timothy T
AU  - Cornell TT
AD  - 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
FAU - Rodenhouse, Paul
AU  - Rodenhouse P
FAU - Cai, Qing
AU  - Cai Q
FAU - Sun, Lei
AU  - Sun L
FAU - Shanley, Thomas P
AU  - Shanley TP
LA  - eng
GR  - K08 GM076344/GM/NIGMS NIH HHS/United States
GR  - R01 GM066839/GM/NIGMS NIH HHS/United States
GR  - K12GM076344/GM/NIGMS NIH HHS/United States
GR  - R01GM66839/GM/NIGMS NIH HHS/United States
GR  - K08 HD062142/HD/NICHD NIH HHS/United States
GR  - K12 HD047349/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20100329
PL  - United States
TA  - Infect Immun
JT  - Infection and immunity
JID - 0246127
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
RN  - EC 3.1.3.48 (Dusp1 protein, mouse)
RN  - EC 3.1.3.48 (MKP2 protein, mouse)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
SB  - IM
MH  - Animals
MH  - Bacterial Infections/immunology
MH  - Cytokines/blood
MH  - Dual Specificity Phosphatase 1/analysis
MH  - Female
MH  - Inflammation/*immunology
MH  - Lipopolysaccharides/immunology/toxicity
MH  - MAP Kinase Kinase 4/analysis
MH  - Macrophages/chemistry/immunology
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Peritonitis/immunology
MH  - Protein Tyrosine Phosphatases/deficiency/*immunology
MH  - Sepsis/*immunology
MH  - Survival Analysis
MH  - p38 Mitogen-Activated Protein Kinases/analysis
PMC - PMC2876557
EDAT- 2010/03/31 06:00
MHDA- 2010/06/02 06:00
PMCR- 2010/12/01
CRDT- 2010/03/31 06:00
PHST- 2010/03/31 06:00 [entrez]
PHST- 2010/03/31 06:00 [pubmed]
PHST- 2010/06/02 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - IAI.00018-10 [pii]
AID - 0018-10 [pii]
AID - 10.1128/IAI.00018-10 [doi]
PST - ppublish
SO  - Infect Immun. 2010 Jun;78(6):2868-76. doi: 10.1128/IAI.00018-10. Epub 2010 Mar 
      29.