| Project/Area Number |
05670438
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
内科学一般
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| Research Institution | University of Occupational & Environmental Health (U.O.E.H.) |
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Principal Investigator |
TANAKA Yoshiya U.O.E.H., Medicine, Instructor, 医学部, 助手 (30248562)
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| Co-Investigator(Kenkyū-buntansha) |
SHIRAKAWA Fumihiko U.O.E.H., Medicine, Assist.Prof., 医学部, 講師 (10158967)
OTA Toshiyuki U.O.E.H., Medicine, Assoc.Prof, 医学部, 助教授 (10140930)
ETO Sumiya U.O.E.H., Medicine, Professor, 医学部, 教授 (90010347)
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| Project Period (FY) |
1993 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1993: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | rheumatoid arthritis / T lymphocyte / endothelium / adhesion molecules / integrin / proteoglycan / MIP-1beta / IL-1 / T細胞 / 滑膜細胞 / サイトカイン / ケモカイン |
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| Research Abstract |
Synovitis in rheumatoid arthritis (RA) is characterized by infiltration of synovium by T cells as well as the proliferation of synovial lining cells. We have studied the mechanism of circulating T cell migration into synovial tissue and interaction of T cells with synovial cells from the standpoints of adhesion molecules, cytokines and proteoglycan.
1.The mechanisms of T cell infiltration into rheumatoid synovium.
We have studied the mechanism of T cell adhesion to endothelium and have proposed that it consists of inflammatory adhesion cascade. To clarify the mechanism of T cell migration into synovial tissue, we assessed the adhesion of peripheral T cells to endothelial cells purified from rheumatoid synovium. The endothelial cells expressed heparan sulfate proteoglycan as well as adhesion molecules such as ICAM-1, VCAM-1 and E-selectin. T cells in synovium produced large amounts of inflammatory cytokine MIP-1beta. The MIP-1beta was most effective when immobilized on the heparan sulfate
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expressed on the rheumatoid endothelium to trigger T cell integrin which lead to the induction of high affinity adhesion of T cells to the endothelium. We reasoned that, as cytokines in vivo will be rapidly washed away by blood flow, MIP-1beta can induce T cell adhesion in its immobilized form. The induced T cell adhesion was inhibited by either, the mixture of anti-VLA-4/LFA-1 antibodies, xyloside which inhibits the synthesis of heparan sulfate, or pertussis toxin which blocks signal transduction through G-protein coupled MIP-1beta receptor. These results indicate that MIP-1beta produced from synovial T cells induces integrin-mediated T cell adhesion to endothelium by its immobilized form on heparan sulfate on synovial endothelium. Thus, cytokines and proteoglycan as well as adhesion molecules are involved in T cell migration into synovium, which leads to accumulation of T cells in rheumatoid synovium. Extrapolation to include the results would bring new approaches to clarification of pathogenesis and pharmacological agents in RA.
2.The mechanisms of cellular interaetion of T cells with synovial cells
Synovial lining cells and T cells play a central role in rheumatoid synovitis. We studied the interaction between T cells and synovial fibroblasts. T cells adhered to the synovial cells mainly through LFA-1/ICAM-1. Histochemical studies indicated that LFA-1-positive T cells accumulated around ICAM-1-positive synovial cells. We found that T cells activated synovial cells to induce IL-1beta production through the cellular adhesion via LFA-1/ICAM-1. To clarify if ICAM-1 per se on the synovial cells induce activation signals, ICAM-1 on a synovial fibroblast cell line established rocally was cross-linked and IL-1beta production was assessed. Cross-linked ICAM-1 induced transcription of IL-1beta genomic DNA through enhancer regions containing nuclear factor AP-1-binding sites by CAT analysis. The involvement of AP-1 in ICAM-1-induced IL-1beta transcription was confirmed by bandshift assay. These results indicate that adhesion molecules not only function as glue but transduce activation signals which induce cytokine production through nuclear factor in rheumatoid synovial cells. Thus, the significance of T cell adhesion to synovial cells by LFA-1/ICAM-1 pathway in the pathogenesis of synovitis is suggested, which may bring new approaches to the control of synovitis. Less
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