17,18-Epoxyeicosatetraenoic Acid Targets PPARγ and p38 Mitogen–Activated Protein Kinase to Mediate Its Anti-inflammatory Effects in the Lung

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.

Arachidonic Acid-metabolizing Cytochrome P450 Enzymes Are Targets of ω-3 Fatty Acids*

“…A recent study revealed that 17,18-EEQ is also a potent regulator of human lung inflammation, and it remains to be seen whether this EPA metabolite may provide protection against critical inflammatory bronchial disorders (76). In the brain, EETs are involved in neurovascular signaling (77) and neuroprotection (78).…”

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

“…The epoxy-metabolites of all three PUFAs share vasodilatory properties, whereby the potencies of EEQs and EDPs may largely exceed those of EETs in some vascular beds ( 18,25 ). Anti-infl ammatory effects were fi rst revealed for 11,12-and 14,15-EET but are also exerted by EPA-epoxides, as exemplifi ed by 17,18-EEQ ( 26,27 -and isoproterenol-induced increased contractility of neonatal cardiomyocytes, indicating that these metabolites may act as endogenous antiarrhythmic agents ( 22 ). Whereas certain EET regioisomers promote tumor angiogenesis and metastasis, 19,20-EDP and other regioisomeric DHA-epoxides inhibit these crucial events in cancerogenesis ( 28,29 ).…”

Lipoxin Generation Is Related to Soluble Epoxide Hydrolase Activity in Severe Asthma

“…Relationship between LXA 4 Levels and sEH Activity sEH expression is increased by oxidative stress (21), abundant in asthmatic airways (22), and its activity can influence LX generation by human cells in vitro and in rodent lung in vivo (18, 23), so we next determined if there was a relationship between LXA 4 levels and sEH activity in the sputum supernatants from subjects with asthma ( Figure 3). Because 14,15-EET is a prominent cytochrome P-450-derived eicosanoid in the lung that is converted by sEH to 14,15-DHET (24), the product/ precursor ratio of 14,15-DHET to 14,15-EET was used as an index for sEH activity.…”