Inhibition of Transcription factor NFkB by methionine-redox

中性粒细胞是白细胞中的一种，在宿主防御细菌感染中起着重要作用。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）。盐酸是一种强氧化剂，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立即反应，形成牛磺酸氯胺（TauCl），其毒性远低于HClO。然而，TauCl的进一步生物活性尚不清楚。当中性粒细胞吞噬入侵细菌时，核因子κB （NFκB）被激活。NFκB是炎症的重要转录因子之一。在本研究项目中，我们研究了TauCl与NFκB活化的相互作用。NFκB存在于细胞质中，作为一种无活性的三级复合体与抑制蛋白称为i - κ b。刺激后，i - κ b被蛋白酶体磷酸化和降解，导致nf - κ b活化。TauCl在蛋氨酸45处氧化i - κ b （1 - κ3α）的a型异构体形成亚砜，抑制其蛋白酶体依赖性降解。这种抑制抑制了nf - κ b的激活，导致中性粒细胞中nf - κ b依赖性炎症细胞因子如白细胞介素8的产生。这是牛磺酸抗炎活性的分子机制之一。嗜酸性粒细胞在肺部的募集和随后的积累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可以减轻哮喘发作。在嗜酸性粒细胞中，存在嗜酸性过氧化物酶（EPO），而不是MPO和产生次溴酸（HBrO）来攻击微生物。牛磺酸与HBrO反应生成牛磺酸溴（TauBr）。我们检查了TauBr是否像TauCl一样抑制NFκB的激活。与TauCl类似，TauBr抑制NFκB活化。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。通常认为牛磺酸具有防止细胞凋亡的功能。中性粒细胞消灭细菌后，易发生细胞凋亡。由于活化NFκB可阻止细胞凋亡，TauCl可能通过抑制NFκB促进细胞凋亡。TauCl通过抑制NFκB来减弱FLICE抑制蛋白短形式的表达。此外，TauCl激活了cJun n末端激酶。这些数据表明TauCl通过两种独立的细胞信号启动中性粒细胞的凋亡。少

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