| 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. | |
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MedLine Citation:
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PMID: 20008283 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Caroline Morin; Marco Sirois; Vincent Echavé; Roula Albadine; Eric Rousseau |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-11 |
Journal Detail:
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Title: American journal of respiratory cell and molecular biology Volume: 43 ISSN: 1535-4989 ISO Abbreviation: Am. J. Respir. Cell Mol. Biol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-25 Completed Date: 2010-11-10 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8917225 Medline TA: Am J Respir Cell Mol Biol Country: United States |
Other Details:
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Languages: eng Pagination: 564-75 Citation Subset: IM |
Affiliation:
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Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec,, J1H 5N4 Canada. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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8,11,14-Eicosatrienoic Acid
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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 Lung / drug effects, enzymology, pathology* Models, Biological 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* |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents; 0/Arachidonic Acids; 0/PPAR gamma; 0/PPP1R14A protein, human; 0/Protein Kinase Inhibitors; 0/Tumor Necrosis Factor-alpha; 131339-23-6/17,18-epoxy-5,8,11,14-eicosatetraenoic acid; 7324-41-6/8,11,14-Eicosatrienoic Acid; 7440-70-2/Calcium; 81276-03-1/14,15-epoxy-5,8,11-eicosatrienoic acid; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 3.1.3.16/Phosphoprotein Phosphatases; EC 3.1.3.53/Myosin-Light-Chain Phosphatase; EC 3.1.3.53/PPP1R12A protein, human; EC 3.3.2.-/Epoxide Hydrolases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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