Inhibition of Transcription factor NFkB by methionine-redox

甲硫氨酸氧化还原对转录因子 NFkB 的抑制

• 批准号: 15380088
• 负责人: MIYAMOTO Yusei
• 金额: $ 10.11万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15380088/
• 关键词: NFκB; IκB; taurine chloramine; taurine bromamine; Oxidation of methionine resudue; anti-inflamation; apoptosis; IκBα; サイトカイン; 炎症; メチオニン残基の参加

Neutrophils are one of the white blood cells that have an important role in the host defense against bacterial infection. When neutrophils phagocytose invading bacteria, myeloperoxidase (MPO) mediates production of hypochlorous acid (HClO) from hydrogen peroxide and chloride ion. HClO is a strong oxidant kills phagocytosed bacteria. In neutrophils, taurine is the most abundant free amino acid. Taurine seems to help protect neutrophils against HClO, because taurine instantaneously reacts with HClO and forms taurine chloramine (TauCl) that is by far less toxic than HClO. However, the further biological activity of TauCl has been left unclear.When neutrophils phagocytose invading bacteria, nuclear factor kappa B (NFκB) is activated. NFκB is one of the crucial transcription factors in inflammation. In this research program, we studied interaction of TauCl with NFκB activation. NFκB is present in the cytoplasm as an inactive tertiary complex with inhibitory proteins known as IκBs. Upon stim … More uli, IκB is phosphorylated and degraded by proteasome, leading to activation of NFκB. TauCl oxidized the a isoform of IκB (1κ3α) at methionine 45 to form sulphoxide and inhibited its proteasome-dependent degradation. This inhibition suppressed the activation of NFκB, leading to NFκB-dependent production of inflammatory cytokines like interleukin 8 in neutrophil. This is one of the molecular mechanisms of anti-inflammatory activation of taurine.The recruitment and subsequent accumulation of eosinophils in the lung occur in a number of inflammatory disorders, including asthma. Previous studies reported that taurine mitigates asthma attack. In eosinophils, eosinophil peroxidase (EPO) is present, instead of MPO and hypobromous acid (HBrO) is produced to attack microorganisms. Taurine reacts with HBrO to form taurine bromamine (TauBr). We examined if TauBr suppresses NFκB activation like TauCl. TauBr inhibited NFκB activation similarly to TauCl. Furthermore, TauBr has higher membrane permeability than TauCl, suggesting that TauBr may suppress production of proinflammatory mediators in the airway.It is usually said that taurine functions for cell protection against apoptosis. After neutrophils eliminate bacteria, they are susceptible to apoptosis. Since NFκB activation prevents apoptosis, TauCl may promote apoptosis by inhibition of NFκB. TauCl attenuated expression of FLICE inhibitory protein short form via inhibition of NFκB. Furthermore, TauCl activated cJun N-terminal kinase. These data indicate that TauCl initiates apoptosis of neutrophils via two independent cell signals. Less

中性粒细胞是一种白色血细胞，在宿主防御细菌感染中具有重要作用。当中性粒细胞吞噬入侵细菌时，髓过氧化物酶（MPO）介导过氧化氢和氯离子产生次氯酸（HClO）。HClO是一种强氧化剂，能杀死被吞噬的细菌。在中性粒细胞中，牛磺酸是最丰富的游离氨基酸。牛磺酸似乎有助于保护中性粒细胞免受HClO的侵害，因为牛磺酸与HClO瞬间反应并形成毒性远低于HClO的牛磺酸氯胺（TauCl）。当中性粒细胞吞噬入侵的细菌时，核因子κ B（NFκB）被激活。NFκB是炎症反应中重要的转录因子之一。在本研究中，我们研究了TauCl与NFκB活化的相互作用。NFκB作为与抑制蛋白Iκ B的无活性三级复合物存在于细胞质中。刺激后 ...更多信息 uli，IκB被蛋白酶体磷酸化降解，导致NFκB活化。TauCl在蛋氨酸45位氧化IκB的a亚型（1κ3α）形成亚砜，并抑制其蛋白酶体依赖性降解。这种抑制抑制NFκB B的活化，导致NFκ B依赖性的炎性细胞因子如白细胞介素8在中性粒细胞中的产生。这是牛磺酸抗炎激活的分子机制之一。嗜酸性粒细胞在肺中的募集和随后的积聚发生在许多炎症性疾病中，包括哮喘。以前的研究报告说，牛磺酸减轻哮喘发作。在嗜酸性粒细胞中，存在嗜酸性粒细胞过氧化物酶（EPO），而不是MPO，并产生次溴酸（HBrO）来攻击微生物。牛磺酸与HBrO反应生成牛磺酸溴胺（TauBr）。我们检测了TauBr是否像TauCl一样抑制NFκB活化。TauBr抑制NFκB活化的作用与TauCl相似。此外，TauBr比TauCl具有更高的膜通透性，这表明TauBr可能抑制气道中促炎介质的产生。在中性粒细胞清除细菌后，它们容易发生凋亡。由于NFκB活化阻止细胞凋亡，TauCl可通过抑制NFκB促进细胞凋亡。TauCl通过抑制NFκB减弱FLICE抑制蛋白短型的表达。此外，TauCl激活cJun N-末端激酶。这些数据表明，TauCl通过两个独立的细胞信号启动嗜中性粒细胞的凋亡。少

项目成果

Taurine is involved in oxidation of IκBα at Met45

牛磺酸参与 IκBα Met45 的氧化

• 发表时间: 2003
• 期刊: Advances in Experimental Medicine and Biology 526(Taurine5)
• 作者: Yusei Miyamoto;Atsuhiro Kanayama;Jun-lchiro Inoue;Yoshiko Sugita-Konishi;Makoto Shimizu
• 通讯作者: Makoto Shimizu

Modification of IKBcL by taurine bromamirn inhibits tumor necrosis factor α-induced NF-κB activation.

牛磺酸 bromamirn 对 IKBcL 的修饰可抑制肿瘤坏死因子 α 诱导的 NF-κB 激活。

• 发表时间: 2007
• 期刊: Inflammation Research (in press)
• 作者: Saimi Tokunaga;Atsuhiro Kanayama Yusiro Miyamoto.
• 通讯作者: Atsuhiro Kanayama Yusiro Miyamoto.

Modification of IκBα by taurine bromamine inhibits tumornecrosis factor α-induced NF-κB activation

牛磺酸溴胺修饰 IκBα 抑制肿瘤坏死因子 α 诱导的 NF-κB 激活

• 发表时间: 2007
• 期刊: Inflammation Research (in press)
• 作者: Saimi Tokunaga;Atsuhiro Kanayama;Yusei Miyamoto
• 通讯作者: Yusei Miyamoto

Apoptosis by phagocytosis-related oxidative stress through FLIPs down-regulation and JNK activation

通过 FLIPs 下调和 JNK 激活，吞噬作用相关的氧化应激导致细胞凋亡

• 发表时间: 2007
• 期刊: Journal of Leukocyte Biology 82(11)
• 作者: Atsuhiro Kanayama;Yusei Miyamoto
• 通讯作者: Yusei Miyamoto

Taurine is involved in oxidation of IKBcL at Met45.

牛磺酸参与 IKBcL 在 Met45 处的氧化。

• 发表时间: 2003
• 期刊: Met45. Advances in Experimental Medicine and Biology(Tme 5) 526
• 作者: Yusei Miyamoto;Atsuhiro Kanayama;Jun-Ichiro Inoue;Yoshiko Sugita-Konishi Makoto Shimizu.
• 通讯作者: Yoshiko Sugita-Konishi Makoto Shimizu.