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.
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.
Morin
Caroline
C
Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec,, J1H 5N4 Canada.
Sirois
Marco
M
Echavé
Vincent
V
Albadine
Roula
R
Rousseau
Eric
E
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008954:Models, Biological; D009124:Muscle Proteins; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D047495:PPAR gamma; C107507:PPP1R14A protein, human; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C070378:17,18-epoxy-5,8,11,14-eicosatetraenoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D002118:Calcium