title: Arsenic trioxide prevents nitric oxide production in lipopolysaccharide -stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway.
abstract: Arsenic trioxide (ATO) is one of the most potent drugs in cancer chemotherapy, and is highly effective in treating both newly diagnosed and relapse patients with acute promyelocytic leukemia (APL). Despite a number of reports regarding the molecular mechanisms by which ATO promotes anti-tumor or pro-apoptotic activity in hematological and other solid malignancies, the effects of ATO on immune responses remain poorly understood. To further understand and clarify the effects of ATO on immune responses, we sought to examine whether ATO affects the production of nitric oxide (NO) in a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line, RAW 264.7. Arsenic trioxide was found to prevent NO production in a dose-dependent manner. Arsenic trioxide significantly inhibited the increase in inducible nitric oxide synthase (iNOS) at both the mRNA and protein levels. Furthermore, our analyses revealed that the inhibitory effect of ATO on iNOS expression was ascribed to the prevention of IRF3 phosphorylation, interferon (IFN)-β expression, and STAT1 phosphorylation, but not the prevention of the MyD88-dependent pathway. Taken together, our results indicate that ATO prevents NO production by inhibiting the TIR-domain-containing adaptor protein inducing IFN-β (TRIF)-dependent pathway, thus highlighting an anti-inflammatory property of ATO in innate immunity.
authors.affiliation: Department of Biochemistry, Department of Internal Medicine, Nagakute, Aichi, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Akinobu
authors.initials: A
authors.lastname: Ota
authors.forename: Sivasundaram
authors.initials: S
authors.lastname: Karnan
authors.forename: Ekhtear
authors.initials: E
authors.lastname: Hossain
authors.forename: Yuko
authors.initials: Y
authors.lastname: Konishi
authors.forename: Lkhagvasuren
authors.initials: L
authors.lastname: Damdindorj
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokochi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Nitta
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hosokawa
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D020929:Mitogen-Activated Protein Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D010087:Oxides; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C494080:Stat1 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C496317:Nos2 protein, mouse