title: 15-Hydroxyprostaglandin dehydrogenase generation of electrophilic lipid signaling mediators from hydroxy ω-3 fatty acids.
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.
authors.affiliation: From the Department of Pharmacology and Chemical Biology and gstacy@pitt.edu.
authors.forename: Stacy Gelhaus
authors.initials: SG
authors.lastname: Wendell
authors.affiliation: From the Department of Pharmacology and Chemical Biology and.
authors.forename: Franca
authors.initials: F
authors.lastname: Golin-Bisello
authors.affiliation: Asthma Institute and Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Sally
authors.initials: S
authors.lastname: Wenzel
authors.affiliation: From the Department of Pharmacology and Chemical Biology and University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania 15213.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.affiliation: Asthma Institute and Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Fernando
authors.initials: F
authors.lastname: Holguin
authors.affiliation: From the Department of Pharmacology and Chemical Biology and freerad@pitt.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
mesh_terms: D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D034622:RNA Interference; D012137:Respiratory System / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013379:Substrate Specificity
chemical_list: D016207:Cytokines; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D008055:Lipids; D008070:Lipopolysaccharides; D004281:Docosahexaenoic Acids; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase
keywords: Eicosanoid; Fatty Acid Oxidation; Lipid Oxidation; Lipid Signaling; Signaling