| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
CD16 (IgG Fc receptor type IIIA)-expressing CD14+ monocytes express high levels of Toll-like receptor 2 (TLR2) and are able to efficiently produce proinflammatory cytokines such as tumor necrosis factor-α (TNFα). To know the role of CD16 and TLR2 in monocyte and macrophage activation in rheumatoid arthritis (RA), we investigated the expression of TLR2 on CD16+ blood monocytes and synovial tissue macrophages and the effect of CD16 and TLR2 activation on cytokine production. The frequency of CD16+ cells in all blood monocytes was significantly increased in RA patients than in healthy controls (HC). TLR2 was expressed at higher levels on CD16+ monocytes compared with CD16-monocytes, while TLR4 was expressed similarly on both monocytes. In RA synovial tissue, CD16+ TLR2+ cells were distributed mainly in the lining layer. TLR2 expression on monocytes was enhanced by macrophage-colony stimulating factor (M-CSF) and interleukin-10 (IL-10), but reduced by transforming growth factor β1, while C
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D16 expression was inducible by these cytokines. Adhered monocytes (〜50% CD16+) produced TNFα, IL-1β,IL-6,IL-8,IL-12 p40,IL-1 receptor antagonist (IL-1Ra), and IL-10 after lipoteichoic acid (LTA) stimulation. This cytokine response was inhibited significantly by anti-TLR2 Ab and partly by anti-TLR4 Ab. Anti-FcγRIII Ab stimulation markedly enhanced the LTA-induced TNFαresponse. HSP60 could stimulate TNFα production by adhered monocytes, which was inhibited similarly by anti-TLR2 Ab and anti-TLR4 Ab. NF-κB activation in adhered monocytes was induced by LTA, but this NF-κB activity was not augmented by anti-FcγRIII Ab stimulation. In addition, p38-MAP kinase activation was found to be crucial in LTA-stimulated cytokine production in CD16+ monocytes. These results suggest that CD16+ monocytes and synovial tissue macrophages with high TLR2 expression may be induced by M-CSF and IL-10, and their production of TNFα could be simulated by endogenous TLR ligands such as HSP60 and FcγRIIIA ligation by small immune complexes in RA joints. Less
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