Abstract
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.
Highlights
15-Hydroxyprostaglandin dehydrogenase (15PGDH) is the primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites
The incubation of cell-free Hanks’ balanced salt solution or media with docosahexaenoic acid (DHA) resulted in minimal generation of hydroxylated docosahexaenoic acid metabolites (HDoHEs) from DHA autoxidation, whereas the addition of exogenous DHA to primary airway epithelial cell (AEC) resulted in the generation of HDoHEs (Fig. 1B) via enzymatic and non-enzymatic reactions that could be quantitated in the media using 5-oxoETE-d7 as the internal standard (Fig. 1C) (28 –33)
15PGDH is noted for inactivating the pro-proliferative PGE2 and the polyhydroxylated fatty acid derivatives termed lipoxin A4 and resolvin E1
Summary
15-Hydroxyprostaglandin dehydrogenase (15PGDH) catalyzes the oxidation of hydroxylated polyunsaturated fatty acids to ␣,-unsaturated carbonyl-containing electrophiles. 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 LPSinduced proinflammatory cytokine mRNA expression These data reveal that 15PGDH-derived DHA metabolites are biolog-. 15-Hydroxyprostaglandin dehydrogenase (15PGDH) is a key enzyme in prostaglandin metabolism It is responsible for the conversion of prostaglandin (PG) E2, a hydroxylated prostaglandin, to its corresponding oxidized counterpart, 9,15-dioxo-11␣-hydroxy-prosta-5Z,13E-dien-1-oic acid (15-ketoPGE2). This mechanism of oxidation is not specific to PGE2 as 15PGDH is responsible for the conversion of 15(S)-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid and 11(R)-hydroxy-5Z,8Z,12E,14Z-eicosatetraenoic acid to their corresponding keto metabolites, 15- and 11-oxoeicosatetra-
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