17,18-epoxyeicosatetraenoic acid targets PPARγ and p38 mitogen-activated protein kinase to mediate its anti-inflammatory effects in the lung: role of soluble epoxide hydrolase.

Abstract

This study sought to assess putative pathways involved in the anti-inflammatory effects of 17,18-epoxyeicosatetraenoic acid (17,18-EpETE), as measured by a decrease in the contractile reactivity and Ca(2+) sensitivity of TNF-α-pretreated human bronchi. Tension measurements performed in the presence of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a soluble epoxide hydrolase (sEH)-specific inhibitor, demonstrated that 17,18-EpETE reduced the reactivity of TNF-α-pretreated tissues. The overexpression of sEH detected in patients with asthma and TNF-α-treated bronchi contributed to the maintenance of hyperresponsiveness in our models, which involved intracellular proinflammatory cascades. The inhibition of peroxisome proliferator-activated receptor (PPAR)γ by GW9662 abolished 17,18-EpETE + AUDA-mediated anti-inflammatory effects by inducing IκBα degradation and cytokine synthesis, indicating that PPARγ is a molecular target of epoxy-eicosanoids. Western blot analysis revealed that 17,18-EpETE pretreatment reversed the phosphorylation of p38 mitogen-activated protein kinase (p38-MAPK) induced by TNF-α in human bronchi. The Ca(2+) sensitivity of human bronchial explants was also quantified on β-escin permeabilized preparations. The presence of SB203580, a p38-MAPK inhibitor, reversed the effect induced by epoxy-eicosanoid in the presence of AUDA on TNF-α-triggered Ca(2+) hypersensitivity by increasing the phosphorylation level of PKC Potentiated Inhibitor Protein-17 (CPI-17) regulatory protein. Moreover, PPARγ ligands, such as rosiglitazone and 17,18-EpETE, decreased the expression of CPI-17, both at the mRNA and protein levels, whereas this effect was countered by GW9662 treatment in TNF-α-treated bronchi. These results demonstrate that 17,18-EpETE is a potent regulator of human lung inflammation and concomitant hyperresponsiveness, and may represent a valuable asset against critical inflammatory bronchial disorder.

• Authors: Caroline Morin, Marco Sirois, Vincent Echavé, Roula Albadine, Eric Rousseau
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 43 Issue 5 Pg. 564-75 (Nov 2010) ISSN: 1535-4989 [Electronic] United States
• PMID: 20008283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Arachidonic Acids
• Intracellular Signaling Peptides and Proteins
• Muscle Proteins
• PPAR gamma
• PPP1R14A protein, human
• Protein Kinase Inhibitors
• Tumor Necrosis Factor-alpha
• 17,18-epoxy-5,8,11,14-eicosatetraenoic acid
• 14,15-epoxy-5,8,11-eicosatrienoic acid
• Cyclooxygenase 2
• PTGS2 protein, human
• p38 Mitogen-Activated Protein Kinases
• Phosphoprotein Phosphatases
• Myosin-Light-Chain Phosphatase
• PPP1R12A protein, human
• Epoxide Hydrolases
• 8,11,14-Eicosatrienoic Acid
• Calcium

Topics

• 8,11,14-Eicosatrienoic Acid (analogs & derivatives, pharmacology)
• Anti-Inflammatory Agents (pharmacology)
• Arachidonic Acids (antagonists & inhibitors, pharmacology)
• Bronchi (drug effects, enzymology, pathology)
• Calcium (pharmacology)
• Cyclooxygenase 2 (metabolism)
• Epoxide Hydrolases (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins
• Lung (drug effects, enzymology, pathology)
• Models, Biological
• Muscle Proteins
• Myosin-Light-Chain Phosphatase (metabolism)
• PPAR gamma (antagonists & inhibitors, metabolism)
• Phosphoprotein Phosphatases (metabolism)
• Phosphorylation (drug effects)
• Pneumonia (enzymology, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Solubility (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)