Summary
Here we report that Cyclooxygenase-2 (COX-2) mediates the formation of electrophilic fatty acid oxo-derivatives (EFOXs) from the omega-3 fatty acids (ω-3 FA) docosahexaenoic, docosapentaenoic and docosatetraenoic acid. EFOXs produced by activated macrophages were discovered by a mass spectrometry-based “fishing” method, using the nucleophile β-mercaptoethanol (BME) as bait. Intracellular EFOX concentrations ranged from 65 to 350 nM, with acetylsalicylic acid (ASA, aspirin) increasing both rate of production and intracellular concentrations. Due to an electrophilic nature, EFOXs adducted protein cysteine and histidine residues and the cysteine of glutathione (GSH) in activated macrophages. A role for EFOXs as signalling mediators was confirmed by the observations that 17-EFOX-D6 and 17-EFOX-D5 are PPARγ agonists and activate Nrf2-dependent antioxidant responses. They also inhibited cytokine production and inducible nitric oxide synthase (NOS-2) expression in activated macrophages within a biological concentration range. Thus, EFOXs are signalling mediators that can transduce the clinically beneficial effects of ω-3 FA, COX-2 and ASA.
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