S. Wendell, Franca Golin-Bisello, S. Wenzel
Jan 12, 2015
Citations
2
Influential Citations
21
Citations
Quality indicators
Journal
The Journal of Biological Chemistry
Abstract
Background: 15-Hydroxyprostaglandin dehydrogenase (15PGDH) catalyzes the oxidation of hydroxylated polyunsaturated fatty acids to α,β-unsaturated carbonyl-containing electrophiles. Results: Hydroxylated docosahexaenoic acid (DHA) metabolites are substrates for 15PGDH, yielding electrophilic oxoDHA products that are anti-inflammatory. Conclusion: Hydroxylated Ω-3 fatty acid species are conferred with cell signaling capabilities after oxidation by 15PGDH. Significance: Formation of biologically active metabolites by 15PGDH contributes to the salutary signaling actions of Ω-3 fatty acids. 15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites. The oxidation of hydroxylated fatty acids, such as the conversion of prostaglandin (PG) E2 to 15-ketoPGE2, by 15PGDH is viewed to inactivate signaling responses. In contrast, the typically electrophilic products can also induce anti-inflammatory and anti-proliferative responses. This study determined that hydroxylated docosahexaenoic acid metabolites (HDoHEs) are substrates for 15PGDH. Examination of 15PGDH substrate specificity was conducted in cell culture (A549 and primary human airway epithelia and alveolar macrophages) using chemical inhibition and shRNA knockdown of 15PGDH. Substrate specificity is broad and relies on the carbon position of the acyl chain hydroxyl group. 14-HDoHE was determined to be the optimal DHA substrate for 15PGDH, resulting in the formation of its electrophilic metabolite, 14-oxoDHA. Consistent with this, 14-HDoHE was detected in bronchoalveolar lavage cells of mild to moderate asthmatics, and the exogenous addition of 14-oxoDHA to primary alveolar macrophages inhibited LPS-induced proinflammatory cytokine mRNA expression. These data reveal that 15PGDH-derived DHA metabolites are biologically active and can contribute to the salutary signaling actions of Ω-3 fatty acids.