| Project/Area Number |
15590438
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Osaka University |
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Principal Investigator |
HIRATA Takako Osaka University, Research Institute for Microbial Diseases, Designated Associate Professor, 微生物病研究所, 特任助教授 (00346199)
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| Co-Investigator(Kenkyū-buntansha) |
MIYASAKA Masayuki Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (50064613)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | leukocyte rolling / adhesion molecules / selectins / integrins / PSGL-1 / LFA-1 / ICAM-1 / Th1 cells |
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| Research Abstract |
Leukocytes migrate from the blood into non-lymphoid tissues through a multi-step process that involves cell rolling, arrest, and transmigration. Although the role of P-selectin glycoprotein ligand-1 (PSGL-1), a major ligand for P-selectin expressed on leukocytes, as a rolling receptor has been clarified, the mechanisms regulating the PSGL-1-mediated rolling and the transition from rolling to arrest are not well understood. In this research project, we clarified two PSGL-1-mediated mechanisms that can regulate the transition form rolling to arrest. The first mechanism is the PSGL-1-mediated stimulation of LFA-1-dependent cell adhesion. We showed that antibody-mediated cross-linking of the PSGL-1 on Th1 cells enhances LFA-1-dependent cell binding to ICAM-1. Combined stimulation by PSGL-1 cross-linking and the Th1-stimulating chemokine CXCL10 (IP-10) or CCLS (RANTES) showed a more-than additive effect on LFA-1-mediated Th1 cell adhesion as well as on LFA-1 redistribution on the cell surface. Moreover, PSGL-1-mediated rolling on P-selectin enhanced the Th1 cell accumulation on ICAM-1 under flow conditions. These results support the idea that PSGL-1-mediated rolling interactions induce intracellular signals leading to integrin activation, facilitating Th1-cell arrest and subsequent migration into target tissues. The second mechanism is the interaction of PSGL-1 with chemokines. We showed that human PSGL-1 interacts with CCL27 (CTACK), and that sulfated tyrosines play a critical role in the CCL27-PSGL-1 interaction. Functionally, PSGL-1 reduced the chemotaxis of L1.2 cells expressing CCR10, the receptor for CCL27. Regulation of chemokine-mediated responses by PSGL-1 may affect the transition from rolling to chemokine-mediated arrest during leukocyte migration.
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