| Project/Area Number |
07807053
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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 |
内科学一般
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| Research Institution | University of Occupational and Environmental Health |
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Principal Investigator |
ETO Sumiya (1996) University of Ocupational and Environmental Health, The First Department of Internal medicine, Professor, 医学部, 教授 (90010347)
白川 文彦 (1995) 産業医科大学, 医学部, 講師 (10158967)
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| Co-Investigator(Kenkyū-buntansha) |
OTA Toshiyuki University of Ocupational and Environmental Health, Clinical Laboratory, associa, 医学部, 助教授 (10140930)
江藤 澄哉 産業医科大学, 医学部, 教授 (90010347)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Rheumatoid Arthritis / synovial cells / transcriptional factors / cytokines / interleukin-1 / transfection / transcriptional regulation |
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| Research Abstract |
1. IL-1 upregulated IL-1 and IL-6 mRNA expression in synovial cells. In Rheumatoid Arthritis (RA) synovial cells, these mRNA were expressed more rapidly after IL-1 stimulation compared with that in synovial cells from patients with osteoarthritis. It suggested preexsiting transcriptional factors were activated immediately after the stimulation without de novo synthesis of transcrptional factors in RA synovial cells.
2. Besides the stimulation by soluble factors like IL-1, synovial cells were also stimulated through the cellular adhesion. Either the cell adhesion with PMA pretreated T cells or the crosslinking of ICAM-1 molecules on synovial cells resulted in the induction of IL-1 mRNA expression.
3. Then we have established synovial fibroblastic cell line E11 from a patient with RA and analyzed the transcriptional regulation of inflammatory cytokines using CAT and band shift assays. Both the addition of IL-1 and crosslinking of ICAM-1 molecules on the surface of E11 resulted in the upregulation of CAT activitiese of the enhancer region located at the sequences between -3134 and -2729bp upstream of transcriptional initiation site of IL-1beta gene.
4. AP-1 binding site in this region was indispensable for the induction of CAT activitiese by the stimulation. Furthermore, activation of AP-1 protein after stimulation by IL-1 or crosslinking of ICAM-1 was comfirmed by bandshift assay.
These results suggest that activation of AP-1 protein stimulated by soulble factors and cell adhesion play an important role in the pathological upregulation of inflammatory cytokines in RA synovial cells. Inhibition of activation of AP-1 might be a new therapeutic strategy to control the progression of RA.
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