title: 15-Oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways.
abstract: Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic "inactivation" of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic α,β-unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15-oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2-regulated antioxidant responses (AR) and inhibits NF-κB-mediated pro-inflammatory responses via IKKβ inhibition. Inhibition of glutathione S-transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators.
authors.affiliation: University of Pennsylvania, Department of Pharmacology and Center of Excellence in Environmental Toxicology, Philadelphia, PA 19104, USA.
authors.forename: Nathaniel W
authors.initials: NW
authors.lastname: Snyder
authors.affiliation: University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA.
authors.forename: Franca
authors.initials: F
authors.lastname: Golin-Bisello
authors.affiliation: University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: University of Pennsylvania, Department of Pharmacology and Center of Excellence in Environmental Toxicology, Philadelphia, PA 19104, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.affiliation: University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.affiliation: University of Pittsburgh, Department of Pharmacology and Chemical Biology, Pittsburgh, PA 15261, USA. Electronic address: gstacy@pitt.edu.
authors.forename: Stacy Gelhaus
authors.initials: SG
authors.lastname: Wendell
mesh_terms: D000478:Alkylation / Q000235:genetics; D000975:Antioxidants / Q000378:metabolism; D016718:Arachidonic Acid / Q000235:genetics / Q000378:metabolism; D001095:Arachidonic Acids / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D000975:Antioxidants; D001095:Arachidonic Acids; D005231:Fatty Acids, Unsaturated; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D016718:Arachidonic Acid; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D005982:Glutathione Transferase; D051550:I-kappa B Kinase
keywords: 15-KETE; 15-oxoETE; 15PGDH; Bioactive lipid; Electrophile