title: Downregulation of NO and PGE2 in LPS-stimulated BV2 microglial cells by trans-isoferulic acid via suppression of PI3K/Akt-dependent NF-κB and activation of Nrf2-mediated HO-1.
abstract: Little is known about whether trans-isoferulic acid (TIA) regulates the production of lipopolysaccharide (LPS)-induced proinflammatory mediators. Therefore, we examined the effect of TIA isolated from Clematis mandshurica on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production in BV2 microglial cells. We found that TIA inhibited the production of LPS-induced NO and PGE2 without accompanying cytotoxicity in BV2 microglial cells. TIA also downregulated the expression levels of specific regulatory genes such as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) by suppressing LPS-induced NF-κB activity via dephosphorylation of PI3K/Akt. In addition, we demonstrated that a specific NF-κB inhibitor PDTC and a selective PI3K/Akt inhibitor, LY294002 effectively attenuated the expression of LPS-stimulated iNOS and COX-2 mRNA, while LY294002 suppressed LPS-induced NF-κB activity, suggesting that TIA attenuates the expression of these proinflammatory genes by suppressing PI3K/Akt-mediated NF-κB activity. Our results showed that TIA suppressed NO and PGE2 production through the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent heme oxygenase-1 (HO-1). Taken together, our data indicate that TIA suppresses the production of proinflammatory mediators such as NO and PGE2, as well as their regulatory genes, in LPS-stimulated BV2 microglial cells, by inhibiting PI3K/Akt-dependent NF-κB activity and enhancing Nrf2-mediated HO-1 expression.
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 Dong, Jeju 690-756, Republic of Korea.
authors.forename: Matharage Gayani
authors.initials: MG
authors.lastname: Dilshara
authors.affiliation: Division of Wood Chemistry & Microbiology, Department of Forest Products, Korea Forest Research Institute, 57 Hoegiro, Dongdaemun-gu, Seoul 130-712, Republic of Korea.
authors.forename: Kyoung-Tae
authors.initials: KT
authors.lastname: Lee
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 Dong, Jeju 690-756, Republic of Korea.
authors.forename: Rajapaksha Gedara Prasad Tharanga
authors.initials: RG
authors.lastname: Jayasooriya
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 Dong, Jeju 690-756, Republic of Korea.
authors.forename: Chang-Hee
authors.initials: CH
authors.lastname: Kang
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 Dong, Jeju 690-756, Republic of Korea.
authors.forename: Sang Rul
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 614-050, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Microbiology, College of Medicine, Inje University, Busan 614-735, Republic of Korea.
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.affiliation: School of Medicine, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Hyun
authors.affiliation: School of Medicine, Jeju National University, Jeju 690-756, Republic of Korea.
authors.forename: Weon-Young
authors.initials: WY
authors.lastname: Chang
authors.affiliation: Management Strategy Team, Korea Forestry Promotion Institute, Mapo-gu, Seoul 121-914, Republic of Korea.
authors.forename: Yeon-Su
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Division of Wood Chemistry & Microbiology, Department of Forest Products, Korea Forest Research Institute, 57 Hoegiro, Dongdaemun-gu, Seoul 130-712, Republic of Korea.
authors.forename: Hak-Ju
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Laboratory of Immunobiology, Department of Marine Life Sciences, Jeju National University, Ara-1 Dong, Jeju 690-756, Republic of Korea. Electronic address: immunkim@jejunu.ac.kr.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002934:Cinnamates / Q000302:isolation & purification / Q000494:pharmacology*; D039324:Clematis; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000276:immunology; D015536:Down-Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018517:Plant Roots
chemical_list: D000893:Anti-Inflammatory Agents; D002934:Cinnamates; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D015232:Dinoprostone; C008180:isoferulic acid
keywords: Heme oxgenase-1; Nitric oxide; Nuclear factor erythroid 2-related factor 2; Nuclear factor-κB; Prostaglandin E(2); Trans-isoferulic acid