title: HNO suppresses LPS-induced inflammation in BV-2 microglial cells via inhibition of NF-κB and p38 MAPK pathways.
abstract: Both hydrogen sulfide (H2S) and nitric oxide (NO) are important gaseous mediators. We and others previously reported that these two gases react with each other to generate a new mediator, nitroxyl (HNO), and regulate cardiovascular functions. In this study, we demonstrated for the first time that the interaction between the two gases also existed in microglia. The biological functions of HNO in microglial cells were further studied with Angeli's salt (AS), an HNO donor. We found that AS attenuated lipopolysaccharide (LPS)-evoked production of reactive oxygen species (ROS) and pro-inflammatory cytokines (e.g. IL-1β and TNFα) through downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). HNO significantly reduced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the activation of nuclear factor-κB (NF-κB) through suppression of phosphorylation p65 and IκBα. The above effects were abolished by l-cysteine, an HNO scavenger, but were not mimicked by nitrite, another product of AS during generating HNO. A Cys-179-to-Ala mutation in inhibitory κB kinase β (IKKβ) mimicked the effect of HNO on LPS-induced NF-κB activation. Interestingly, AS abolished the inflammation in cells overexpressing WT-IKKβ, but had no significant effect in cells overexpressing C179A-IKKβ. These data suggest that HNO may act on C179 to prevent IKKβ-dependent inflammation. Taken together, our data demonstrated for the first time that H2S interacts with NO to generate HNO in microglial cells. HNO produces anti-inflammatory effects through suppressing the IKKβ dependent NF-κB activation and p38 MAPK pathways.
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
authors: Yebo
authors: Y
authors: Zhou
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
authors: Zhiyuan
authors: Z
authors: Wu
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
authors: Xu
authors: X
authors: Cao
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
authors: Lei
authors: L
authors: Ding
authors: Zhejiang Provincial Engineering Technology Research Center of Marine Biomedical Products, Food and Pharmacy College, Zhejiang Ocean University, Zhoushan 316000, China.
authors: ZhengShun
authors: Z
authors: Wen
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore. Electronic address: phcbjs@nus.edu.sg.
authors: Jin-Song
authors: JS
authors: Bian
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009573:Nitrites; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; C021229:oxyhyponitrite; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; C039900:nitroxyl; D006862:Hydrogen Sulfide
keywords: Angeli’s salt, PubChem CID: CID 10129945; HNO; Inflammation; Inhibitory κB kinase β; Microglial; Nuclear factor-κB; p38 Mitogen-activated protein kinase