| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
A variety of cytokines have been reported to be able to recognize specific carbohydrate moieties. I have found that several cytokines including IL-1β,TNF-α,IL-18 can recognize GPI-anchored glycan. In this research, I investigated whether the carbohydrate recognition by these cytokines can modulate their physiological activities, (i)The stimulation of the apoptosis o human lymphoma U937 cells by TNF-α was inhibited by treatment with mannose 6-phosphate or phosphatidyl inositol-speciic phospholipase C (PI-PLC). These results suggest that TNF-α bindig to the GPI-anchore glycan, along with its binding to TNF-α receptor, triggers the intracellular signaling pathway in U937 cells, (ii)I found that IL-18 and IL-18Rα bind to GPI glycan via the third mannose 6-phosphate diester and the second β-GlcNAc-deleted mannose 6-phosphate of GPI-glycan, respectively. To investigate whether the carbohydrate recognition of IL-18 is involved in physiological activities, KG-1 cells were digested with PI-PLC before IL-18 stimulation. PI-PLC treatment inhibited the phosphorylation of tyrosine kinases and the following IL-18 dependent IFN-γ production. Moreover, IL-18Receptor α subunit of IL-18 stimulated KG-1 cells was immunoprecipitated together CD48 by anti-IL-18Rα antibody. These observations suggest that the complex formation of IL-18/IL-18Rα/CD48 via both the peptide portion and GPI glycan triggers the binding to IL-18Rβ, and IL-18/IL-18Rα/CD48/IL-18Rβ complex induces cellular signaling.
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