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

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.

C1q/TNF-Related Proteins, A Family of Novel Adipokines, Induce Vascular Relaxation Through the Adiponectin Receptor-1/AMPK/eNOS/Nitric Oxide Signaling Pathway

“…These results provide the first direct evidence that AdipoR1 may function as a CTRP9 binding protein. Recently, studies on knockout mice indicate that the two receptors mediate different signaling events in liver, with AdipoR1 primarily acting on AMPK, and AdipoR2 primarily affecting PPARα, 36, 39,40 consistent with our study’s mechanistic data. The adapter protein APPL1, containing a pleckstrin homology domain, a phosphotyrosine-binding domain, and a leucine zipper motif, appears to be a key intracellular effector of adiponectin’s effects, via binding to the N-terminus of AdipoR1.…”

Hypoxia downregulates PPARγ via an ERK1/2–NF-κB–Nox4-dependent mechanism in human pulmonary artery smooth muscle cells

“…For example, hypoxia activates mitogen-activated protein kinases (MAPKs) [17, 18] that regulate the activity of transcription factors such as PPARγ and NF-κB. Hypoxia also activates pro-inflammatory and oxidative stress signals that reduce PPARγ expression and activity [19, 20]. Hypoxia selectively increased Nox4 expression in the pulmonary vasculature [21].…”

Combined Zinc Supplementation With Proinsulin C-Peptide Treatment Decreases the Inflammatory Response and Mortality in Murine Polymicrobial Sepsis

“…To investigate the mechanism of action of the combined treatment, we evaluated the lung nuclear activation of pERK1/2, an important mitogen-activated protein kinase that has been postulated to have a pathological role in sepsis also by mediating PPARγ degradation (15). At Western blot analysis, expression of the active pERK1/2 slightly increased in lung nuclear extracts 18 h after laparotomy (sham) and was significantly enhanced by CLP procedure when compared to baseline expression of control normal mice.…”

“…Consistent with these previous studies, we found that combined treatment of zinc supplementation and C-peptide restored lung nuclear expression of PPARγ, which was associated with a remarkable inhibition of NF-κB activity and subsequent downregulation of the NF-κB dependent pro-inflammatory cytokines, TNF-α and IL-6, and the chemokine MIP-1α. To further define the anti-inflammatory molecular mechanisms of zinc supplementation of C-peptide we also investigated the role of ERK1/2, which have been implicated in the regulation of pro-inflammatory transcription factors and in the pathogenetic events of sepsis (15). In vitro studies in cultured cells have also suggested that ERK1/2 activation may result into PPARγ inactivation, as the kinases induce PPARγ phosphorylation, thus triggering the nuclear receptor for protein degradation (34).…”