| Budget Amount *help |
¥15,800,000 (Direct Cost: ¥15,800,000)
Fiscal Year 2006: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2005: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2003: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Research Abstract |
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
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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
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