Cytokine production by human lung cancer and its paracrine regulation

人肺癌细胞因子的产生及其旁分泌调节

基本信息

批准号：
07670669
负责人：
SONE Saburo
金额：
$ 1.47万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670669/
关键词：
Lung cancer Cytokine Paracrine Macrophage IL-10 MCP-1 IL-1ra 肺胞マクロファージ IL-6 MCAF

项目摘要

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 … More 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

Th2细胞因子（例如IL-4，IL-10和IL-13）抑制单核细胞/巨噬细胞的促炎细胞因子的产生。由于单核细胞介摄蛋白1（MCP-1）在炎症和免疫体验期间在单核细胞募集和激活中起重要作用，因此我们在这里检查了这些Th2细胞因子对人类血液单核细胞和藻类巨性巨噬细胞的MCP-1产生的影响（AM）。未刺激的高度纯化的血液单核细胞不会在LPS治疗诱导MCP-1及其mRNA表达的产生时产生MCP-1。所有TH2细胞因子均已测试，抑制LPS诱导的MCP-1产生及其mRNA表达，尽管IL-13的抑制作用较弱，比IL-4和IL-10的抑制作用弱。 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 maximum level at 12h, IL-10-induced MCP-1 production was reduced by pre-treatment of IL-10 wit … More h anti-IL-10 Ab, negating the involvement of contaminated endotoxin.此外，IL-10在未刺激的单核细胞中诱导MCP-1 mRNA表达，与从头蛋白合成无关。此外，人类AM自发产生MCP-1，并且IL-4或IL-13抑制了生产，但由IL-10增强。 THES的发现表明，IL-10以与其他TH2细胞因子（例如IL-4和IL-13）不同的方式来调节单核细胞/巨噬细胞的MCP-1产生，并有助于宿主的防御反应。我们先前建立的新型转移性转移的人类肺癌模型在NK Cells中销售了Scid小鼠的销售。人肺鳞状细胞癌（RERF-LC-AAI）细胞主要在肝脏和肾脏中形成转移，而小细胞肺癌（H69/VP）细胞主要在NK-Cell-Cell耗尽的Scid小鼠中形成全身性淋巴结和肝脏中的转移。进行了这项研究以探索局部细胞因子产生对转移形成的影响。为了通过转移性癌细胞的局部细胞因子产生积累或激活巨噬细胞，我们将插入PRC/CMV-MCSF的人类M-CSF基因转换为插入BCMGSNEO-MCAF中的人类MCP-1基因为H69/VP和/VP和/或RERF-LC-LC-LC-ai细胞的繁殖。与父母和模拟转导的细胞相比，S.C.注射的M-CSF产生细胞的体内生长较慢。肝脏中MCSF-AI-9-18和MCSF-AI-9-24细胞的转移菌落数量显着降低，但在肾脏中没有显着减少。与父母或模拟转导细胞相比，MCSF-VP细胞的淋巴结转移的数量也受到抑制。用抗H-M-CSF AB得出的NK细胞的SCID小鼠促进了MCSF-AI-9-18和MCSF-AI-9-24细胞的肝转移。使用RH M-CSF（i.p.）的全身治疗对RERF-LC-ai细胞的转移没有影响。相反，MCP-1基因转移到H69/VP细胞中不会影响H69/VP细胞的体内生长或转移潜力。这些发现表明，M-CSF的抗转移性效应可能是器官特异性的，并且局部M-CSF的存在可能具有治疗益处，可以抑制人类肺癌的转移。较少的