| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
Th2 cytokines such as IL-4, IL-10, and IL-13, suppress pro-inflammatory cytokine production by monocytes/macrophages. Since monocyte chemoattractant protein-1 (MCP-1) is presumed to play an important role in monocyte recruitment and activation during inflammatory and immune responses, we examined here the effects of these Th2 cytokines on MCP-1 production by human blood monocytes and alvcolar macrophages (AM). Unstimulated highly purified blood monocytes did not produce MCP-1 spontaneously while LPS treatment induced the production of MCP-1 and its mRNA expression. All Th2 cytokines tested, suppressed LPS-induced MCP-1 production and its mRNA expression although the suppressive effect of IL-13 was weaker than those of IL-4 and IL-10. In contrast, IL-10 but neither IL-4 nor IL-13, induced unstimulated peripheral blood monocytes to produce biologically active MCP-1 protein within 4h, reaching a maximal level at 12h, IL-10-induced MCP-1 production was reduced by pre-treatment of IL-10 wit
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h anti-IL-10 Ab, negating the involvement of contaminated endotoxin. Moreover, IL-10 induced MCP-1 mRNA expression in unstimulated monocytes, independent of de novo protein synthesis. Furthermore, human AM produced MCP-1 spontaneously, and the production was inhibited by IL-4 or IL-13, but rather augmented by IL-10. Thses findings suggest that IL-10 regulates MCP-1 production by monocytes/macrophages in a different way from other Th2 cytokines such as IL-4 and IL-13, and contributes to host defense responses.
We previously established novel metastasis model of human lung cancer sells in SCID mice depleted of NK cells (Yano et al., Int.J.Cancer, 1996). Human lung squamous cell carcinoma (RERF-LC-AI) cells formed metastases mainly in the liver and kidneys whereas small cell lung carcinoma (H69/VP) cells formed metastases mainly in systemic lymphnodes and liver in NK-cell depleted SCID mice. This study was conducted to explore the effect of local cytokine production on metastasis formation. To accumulate or activate macrophages by local cytokine production from metastatic cancer cells, we transduced human M-CSF-gene inserted into pRc/CMV-MCSF or human MCP-1-gene inserted into BCMGSNeo-MCAF to H69/VP and/or RERF-LC-AI cells, respectively.
Cytokine-gene transduction had no effects on expression of surface antigens and proliferation. In vivo growth of s.c.injected M-CSF producing cells in SCID mice was slower when compared with their parent and mock-transduced cells. The number of metastatic colonies of MCSF-AI-9-18 and MCSF-AI-9-24 cells in liver, but not in kidneys, was significantly reduced. The number of lymph node metastases of MCSF-VP cells was also inhibited when compared with their parent or mock-transduced cells. Treatment of SCID mice depleted of NK cells with anti-h-M-CSF Ab promoted liver metastases of MCSF-AI-9-18 and MCSF-AI-9-24 cells. Systemic treatment with rh M-CSF (i.p.) had no effect on metastases of RERF-LC-AI cells. In contrast, MCP-1-gene transduction to H69/VP cells did not affect in vivo growth or metastatic potential of H69/VP cells. These findings suggest that antimetastatic effect of M-CSF may be organ specific and that presence of local M-CSF may have a therapeutic benefit to inhibit the metastases of human lung cancer. Less
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