DNA damage and immunosuppressive cytokines induced by ultraviolet radiation and chemical carcinogen

紫外线和化学致癌物引起的DNA损伤和免疫抑制细胞因子

• 批准号: 14570830
• 负责人: HORIO Takeshi
• 金额: $ 2.5万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570830/
• 关键词: ultraviolet radiation; carcinogenesis; DNA damage; tumor immunity; xeroderma pigmentosum

Ultraviolet radiation(UVR) plays a major role in the development of skin cancers. We have previously reported that a model mice(XPA -/-) of xeroderma pigmentosum group A easily developed skin cancers by exposure to a small amount of UVB or chemical carcinogen(DMBA). DNA damages can cause mutations of tumor suppressor genes or oncogenes. Tumor immunity is important for cancer development and growth. We have demonstrated that contact hypersensitivity and tumor immunity were greatly suppressed by UVR and DMBA in XPA(-/-) mice. Transplanted tumor cells were rejected immunologically from wild type mice as well as XPA(-/-) mice unless exposed to UVB. On the other hand, tumor cells, which were injected into the UVB-irradiated skin of XPA mice, were not rejected and grew to a large tumor. In the present study, we investigated the soluble factors or cytokines which are involved in the UVR-induced immunosuppression. UVB-or DMBA-induced inflammation and immunosuppression were ablogated by pre-treatment of indomethacin which is an inhibitor of prostaglandin synthesis. We further demonstrated that in XPA(-/-)/mice, UVR and DMBA greatly stimulated the expression of mRNA of cyclooxygenase 2,IL-10 and TNFα which have immunosuppressive abilities. These results indicate that DNA damage stimulate the production of immunosuppressive factors and impairs tumor immunity.

紫外线辐射（UVR）在皮肤癌的发展中起着重要作用。我们以前曾报道过A组着色性干皮病模型小鼠（XPA -/-）暴露于少量UVB或化学致癌物（DMBA）容易发生皮肤癌。DNA损伤可引起抑癌基因或癌基因突变。肿瘤免疫对于癌症的发展和生长是重要的。我们已经证明，在XPA（-/-）小鼠中，UVR和DMBA极大地抑制了接触超敏反应和肿瘤免疫。移植的肿瘤细胞从野生型小鼠以及XPA（-/-）小鼠免疫排斥，除非暴露于UVB。另一方面，将肿瘤细胞注射到UVB照射的XPA小鼠皮肤中，没有被排斥并生长成大肿瘤。在本研究中，我们研究了可溶性因子或细胞因子参与紫外线诱导的免疫抑制。用前列腺素合成抑制剂吲哚美辛预处理可消除UVB或DMBA诱导的炎症和免疫抑制。结果表明，在XPA（-/-）/小鼠中，UVR和DMBA可显著刺激具有免疫抑制作用的COX 2、IL-10和TNFα mRNA的表达。这些结果表明，DNA损伤刺激免疫抑制因子的产生并损害肿瘤免疫。