Phosphorylation of Extracellular Signal-Regulated Kinase (ERK)-1/2 Is Associated with the Downregulation of Peroxisome Proliferator-Activated Receptor (PPAR)-gamma during Polymicrobial Sepsis

作者：Kaplan Jennifer M^*; Hake Paul W; Denenberg Alvin; Nowell Marchele; Piraino Giovanna; Zingarelli Basilia

来源：Molecular Medicine, 2010, 16(11-12): 491-497.

DOI：10.2119/molmed.2010.00063

Peroxisome proliferator-activated receptor (PPAR)-gamma is a ligand-activated transcription factor and regulates inflammation. Posttranslational modifications regulate the function of PPAR gamma, potentially affecting inflammation. PPAR gamma contains a mitogen-activated protein kinase (MAPK) site, and phosphorylation by extracellular signal-regulated kinase (ERK)-1/2 leads to inhibition of PPAR gamma. This study investigated the kinetics of PPAR gamma 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 PPAR gamma were decreased and associated with an increase in phosphorylated PPAR gamma and phosphorylated ERK1/2 levels. Treatment with the MEK1 inhibitor increased the antiinflammatory plasma adipokine adiponectin, restored PPAR gamma expression in PBMCs and lung, and decreased lung injury. The inflammatory effects of sepsis cause changes in PPAR gamma expression and activation, in part, because of phosphorylation of PPAR gamma by ERK1/2. This phosphorylation can be reversed by ERK1/2 inhibition, thereby improving lung injury.

• 出版日期2010-12