| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 1999: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1998: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1997: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
Apoptosis is important for the resolution of chronic eosinophilic inflammation observed in bronchial asthma. Using a human myeloblastic leukemia cell line, EoL-1, we investigated the effect of interferon-gamma (IFN-γ) on Fas- and tumor becrosis factor-α (TNF)-induced apoptosis. Both THN and anti-Fas monoclonal antibody (CH-11) induced apoptosis of EoL-1 cells. Pretreatment with IFN-γ enhanced the CH-11-induced apoptosis with up-regulation of Fas. However, the treatment markedly inhibited the TNF-induced apoptosis. In flow cytometric analysis, EoL-1 expressed two types of tumor necrosis factor receptors (TNFR1, 2) and the expression of TNFR2 but not of TNFR1 was up-regulated significantly after the IFN-Γ treatment. The TNF-induced apoptosis was mimicked by a TNFR1 stimulating antibody (htr-9), and was reversed by a TNFR1 blocking antibody (H398). Although the TNFR1-mediated cytotoxic signal was not affected by IFN-γ pretreatment, blocking TNFR2 by a specific antagonistic antibody (utr-1
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) canceled the inhibitory effect of IFN-Γ. In conclusion, TNF-induced apoptosis was mediated preferentially by TNFR1, and the anti-apoptotic effect of IFN-γ result from up-regulated TNFR2 in EoL-1 cell line. Further, we investigated the signal transduction pathway from TNFR2 in IFN-γ treated EoL-1 cells. We revealed that the stimulation through TNFR2 activated the NF-kappaB by western blot analysis.
Recently, we reported that the effect of Rho/ROCK signaling on cell functions. Rho/Rock signaling inhibited the myosin phosphatase and kept the phosphoryrated myosin high. ROCK inhibitor (Y-27632) relaxed the muskarinic bronchiai smooth muscle contraction. Myosin is known to regulates the morphological change and migration of cells. So, we investigated the effect of ROCK inhibitor (Y-27632) on migration of eosinophols and found that Y-27632 inhibitted the migration of eosinophils without inhibitting the CaィイD1++ィエD1 influx or production of active oxygen. These findings were preparing for paper. Less
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