| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
We previously demonstrated that activated human T cells expressing the receptor activator of NF-κB (RANKL) directly induce osteoclastogenesis from human monocytes. The current study explored our hypothesis that IFN-γ-producing T cells inhibit osteoclast formation.
Activated T cells derived from human peripheral blood were divided into IFN-γ-producing T cells [IFN-γ(+) T cells] and IFN-γ-non-producing T cells [IFN-γ(-) T cells]. IFN-γ(+) T cells or IFN-γ(-) T cells were cultured with human monocytes from PBMC in the presence of M-CSF alone. The expression of IFN-γ, IL-4, or RANKL on T cells was detected by flow cytometry. The concentration of soluble RANKL or IFN-γ and the amount of membrane type RANKL expressed on T cells were measured by ELISA. In 15 patients with RA treated with NSAIDs alone and not receiving DMARDs or prednisone and 11 patients with OA, CD4+T cells expressing both IFN-γ and RANKL were detected by flow cytometry.
Surprisingly, IFN-γ(+) T cells, but not IFN-γ(-) T cells, induced osteoclastogenesis from monocytes in the presence of M-CSF alone, which was completely inhibited by adding osteoprotegerin. In addition, the osteoclastogenesis induced by IFN-γ(+) T cells was increased by adding anti-IFN-γ antibodies. IFN-γ(+) T cells included T cells identified as Th1 cells by flow cytometry. In addition, 100pg/ml of IFN-γ, which was a sufficient concentration to inhibit osteoclastogenesis, was detected in the culture supernatants of IFN-γ(+) T cells by ELISA. The levels of both soluble and membrane type RANKL were elevated in IFN-γ(+) T cells. The ratio of CD4+T cells expressing both IFN-γ and RANKL In total CD4+T cells from peripheral blood was significantly higher in RA patients than in OA patients.
Contrary to our hypothesis, these findings demonstrated that IFN-γ(+) T cells induce osteoclastogenesis through the expression of RANKL, suggesting that Th1 cells play a direct role in bone resorption in Th1 dominant diseases such as RA.
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