title: Pinosylvin suppresses LPS-stimulated inducible nitric oxide synthase expression via the MyD88-independent, but TRIF-dependent downregulation of IRF-3 signaling pathway in mouse macrophage cells.
abstract: Since inhibitors of inducible nitric oxide synthase (iNOS) have been considered as potential anti-inflammatory and cancer chemopreventive agents, we have evaluated the inhibitory effects on the production of nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells with natural and synthetic compounds. Pinosylvin (3,5-dihydroxy-trans-stilbene), a stilbenoid mainly found in heartwood of Pinus sylvestris, exhibited the inhibition of iNOS protein and mRNA expression. The plausible mechanisms of pinosylvin on the suppression of iNOS gene expression were found to be associated with the downregulation of interferon regulatory factor 3 (IRF-3) and interferon-β (IFN-β) expression, which are related to Toll/IL-1 receptor domain-containing adapter inducing interferon-β (TRIF)-mediated signaling. Decreased IFN-β expression suppressed a phosphorylation of JAK kinase, and subsequently, the phosphorylation of signal transducer and activator of transcription-1, one of the iNOS transcriptional activators, was inhibited by pinosylvin. In addition, the suppression of poly(I:C)-induced iNOS expression, and the attenuation of iNOS expression under the IRF-3 gene knock-down condition also confirmed that pinosylvin affects TRIF pathway. These findings demonstrate that the suppression of LPS-induced iNOS expression by pinosylvin is associated with the regulation of MyD88-independent, but TRIF-mediated signaling pathway.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Chung
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Ahn
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Pyee
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016899:Interferon-beta / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D000094162:Phytoalexins
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D053612:Janus Kinases; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D034741:RNA, Small Interfering; D013267:Stilbenes; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C049032:pinosylvin; D000094162:Phytoalexins