Document Detail

Phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 Is associated with the downregulation of peroxisome proliferator-activated receptor (PPAR)-γ during polymicrobial sepsis.
MedLine Citation:
PMID:  20809049     Owner:  NLM     Status:  MEDLINE    
Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor and regulates inflammation. Posttranslational modifications regulate the function of PPARγ, potentially affecting inflammation. PPARγ contains a mitogen-activated protein kinase (MAPK) site, and phosphorylation by extracellular signal-regulated kinase (ERK)-1/2 leads to inhibition of PPARγ. This study investigated the kinetics of PPARγ expression and activation in parenchymal and immune cells in sepsis using the MAPK/ERK kinase (MEK)-1 inhibitor, an upstream kinase of ERK1/2. Adult male Sprague Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture. Rats received intraperitoneal injection of vehicle or the MEK1 inhibitor PD98059 (5 mg/kg) 30 min before cecal ligation and puncture. Rats were euthanized at 0, 1, 3, 6 and 18 h after cecal ligation and puncture. Control animals used were animals at time 0 h. Lung, plasma and peripheral blood mononuclear cells (PBMCs) were collected for biochemical assays. In vehicle-treated rats, polymicrobial sepsis resulted in significant lung injury. In the lung and PBMCs, nuclear levels of PPARγ were decreased and associated with an increase in phosphorylated PPARγ and phosphorylated ERK1/2 levels. Treatment with the MEK1 inhibitor increased the antiinflammatory plasma adipokine adiponectin, restored PPARγ expression in PBMCs and lung, and decreased lung injury. The inflammatory effects of sepsis cause changes in PPARγ expression and activation, in part, because of phosphorylation of PPARγ by ERK1/2. This phosphorylation can be reversed by ERK1/2 inhibition, thereby improving lung injury.
Jennifer M Kaplan; Paul W Hake; Alvin Denenberg; Marchele Nowell; Giovanna Piraino; Basilia Zingarelli
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-08-19
Journal Detail:
Title:  Molecular medicine (Cambridge, Mass.)     Volume:  16     ISSN:  1528-3658     ISO Abbreviation:  Mol. Med.     Publication Date:    2010 Nov-Dec
Date Detail:
Created Date:  2010-11-05     Completed Date:  2011-02-17     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  9501023     Medline TA:  Mol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  491-7     Citation Subset:  IM    
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
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MeSH Terms
Adiponectin / blood
Anti-Inflammatory Agents / pharmacokinetics
Lung / physiopathology
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors,  metabolism*
Mitogen-Activated Protein Kinases / metabolism
PPAR gamma / metabolism*
Rats, Sprague-Dawley
Sepsis / metabolism,  microbiology*
Transcription Factors / metabolism
Grant Support
K08 GM093135/GM/NIGMS NIH HHS; K08 GM093135-01/GM/NIGMS NIH HHS; K08 GM093135-02/GM/NIGMS NIH HHS; K08GM093135/GM/NIGMS NIH HHS; K12 HD-028827/HD/NICHD NIH HHS; R01 GM-067202/GM/NIGMS NIH HHS; R01 GM067202-08/GM/NIGMS NIH HHS; T32 ES-10957/ES/NIEHS NIH HHS
Reg. No./Substance:
0/Adiponectin; 0/Anti-Inflammatory Agents; 0/Ligands; 0/PPAR gamma; 0/Transcription Factors; EC Protein Kinase 3; EC Protein Kinases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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