| Co-Investigator(Kenkyū-buntansha) |
HAZEKI Osamu HIROSHIMA UNIV., PROFESSOR, 医学部・総合薬学部・薬効解析化学講座, 教授
枦木 修 広島大学, 医学部・総合薬学学科, 教授 (80142751)
松本 美佐子 大阪府立成人病センター研究所, 第6部, 主任研究員
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| Budget Amount *help |
¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1999: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Research Abstract |
Human CD46, formerly membrane co factor protein (MCP), binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity including down-regulation of IL-12 production has been reported on macrophages (Mφ) by crosslinking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. Here, we found that 6-8 day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and nitric oxide (NO). Within the same time frame, Mφ acquired the capacity to assemble CD9, alphaS betal integrin to their CD46. Mφ earlier to this maturation stage were able to potentiate MV (Edmonston and Nagahata strain) replication, but in the activation stage NO and cytokines were induced and MV replication was severely suppressed. Direct ligation of CD46 by C3b, mAbs F(ab')_2 or MV H/F glycoproteins, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6-8 day GM-CSF-cultured Mφ while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. Taken together, CD46 first serves as a receptor for MV, then recruits a molecular complex as depending upon maturation stages of human Mφ. These results provide strong evidence that CD46 serves as a signal-transducing molecule and that the properties of ligands determine suppression or activation of innate immune system. MV-mediated immune suppression may in part be attributable to the CD46 signaling.
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