| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Interleukin-12 (IL-12) was able to induce interferon-γ (IFN-γ) production by synovial tissue T cells of rheumatoid arthritis (RA). IL-18 had no direct IFN-γ-inducing activity, but IL-12-induced IFN-γ production was enhanced by IL-18, and was significantly diminished in the presence of anti-IL-18 antibody (Ab). Therefore, an abundance of IL-18 in RA joints appears to increase the responsiveness of Th1 cells to IL-12, thereby inducing the local IFN-γ synthesis in the paucity of IL-12.
Cell surface expression of IL-12 receptor (IL-12R) β1/2 chains was undetectable on peripheral blood CD4+ T cells, but it was induced after anti-CD3 Ab stimulation. The induction of IL-12R was stronger in RA patients than in normal subjects. In the synovial tissue, both IL-12Rβ1/2 chains were expressed in a proportion of CD4+ T cells, and mRNA transcripts of the inducible β2 chain were detected. IL-12R expression on synovial tissue CD4+ T cells was enhanced by costimulation with anti-CD3 Ab and IL-18. On the
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other hand, DL-1 8Rα/β chains were constitutively expressed in peripheral blood CD4+ T cells, and the level of expression was greater in RA patients than in normal subjects and was further increased in RA synovial tissues. IL-12βl/2 chains were induced mainly in IL-18Rα-expressing CD4+ T cells, and synovial tissue CD4+ T cells are able to mostly express IL-18Rα and to predominantly produce IFN-γ when activated. IL-12 and IL-18 induced the activation of transcription factors STAT4 and NF-kB in T cells, respectively. These findings indicate that IL-18R+ CD4+ T cells are accumulated in the synovial tissue, where the functional IL-12R may be induced in a proportion of these cells by stimuli such as CD 3 activation and IL-18. Coexpression of IL-12R and IL-18R may be required for IFN-γ-production by Th1 cells in RA.
Furthermore, we found the increased expression of CXCR3 chemokine receptor by RA synovial T cells., and that the ability of CD4+ T cells to express the Th2-related surface molecule CD30 was diminished in RA and CD30+ CD4+T cells of RA could be removed when activated through apoptosis. Less
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