title: Role of Nrf2 in suppressing LPS-induced inflammation in mouse peritoneal macrophages by polyunsaturated fatty acids docosahexaenoic acid and eicosapentaenoic acid.
abstract: This study is to investigate the role of Nrf2 in suppressing LPS-mediated inflammation in ex vivo macrophages by polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Primary peritoneal macrophages from Nrf2 wild-type (+/+; WT) and Nrf2 knockout (-/-; KO) mice were treated with lipopolysaccharides (LPS) in the presence or absence of DHA or EPA. Quantitative real-time PCR (qPCR) analyses showed that LPS potently induced cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in the macrophages collected from Nrf2 (+/+) wild-type mice. DHA and EPA inhibited LPS-induced COX-2, iNOS, IL-1β, IL-6, or TNF-α, but increased hemeoxygenase (HO-1) expression. DHA was found to be more potent than EPA in inhibiting COX-2, iNOS, IL-1β, IL-6, and TNF-α mRNA expression. DHA and EPA were also found to induce HO-1 and Nrf2 mRNA with a different dose-response. LPS induced COX-2, iNOS, IL-1β, IL-6, and TNF-α in the macrophages collected from Nrf2 (-/-) mice as well, however, DHA and EPA suppression of COX-2, iNOS, IL-1β, IL-6, and TNF-α was attenuated as compared to that in Nrf2 (+/+) macrophages. Taken together, using Western blotting, ELISA and qPCR approaches coupled with Nrf2 (-/-) mice, our study clearly shows for the first time that DHA/EPA would induce Nrf2 signaling pathway and that Nrf2 plays a role in DHA/EPA suppression of LPS-induced inflammation.
authors.affiliation: Graduate Program in Pharmaceutical Sciences, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Constance Lay Lay
authors.initials: CL
authors.lastname: Saw
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.forename: Tienyuan
authors.initials: T
authors.lastname: Wu
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D051546:Cyclooxygenase 2; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D051547:Heme Oxygenase-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C495636:Nfe2l2 protein, mouse; C077623:Ptgs2 protein, mouse