Abstract
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.
Highlights
Peroxisome proliferator–activated receptor (PPAR)-γ is a ligand-activated transcription factor
To gain further insights into the molecular mechanisms involved in the decreased nuclear PPARγ content, we evaluated the effect of cecal ligation and puncture (CLP) on p-ERK1/2
The downregulation of PPARγ involves its phosphorylation by ERK1/2, and inhibition of ERK1/2 causes a decrease in phosphorylated PPARγ and restores PPARγ
Summary
Peroxisome proliferator–activated receptor (PPAR)-γ is a ligand-activated transcription factor. Activation of PPARγ plays a role in controlling the inflammatory response. Several studies have demonstrated that activation of PPARγ by specific ligands significantly improves survival in clinically relevant models of septic shock [1,2,3]. The beneficial effect of PPARγ activation is likely to be secondary to inhibition of the production of several inflammatory mediators, as shown in vivo in septic rodents [1,2,3] and in vitro in activated macrophages and monocytes [4]. Sepsis and other inflammatory states affect PPARγ expression and correlate with the inflammatory response. We have previously demonstrated that PPARγ expression is downregulated in the lung and vascular endothelium in rodent models of septic shock and that treatment with PPARγ ligands reverses the sepsis-induced reduction [1]. PPARγ expression decreased after mice were challenged in vivo with endotoxin, and cytokine-induced sup-
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