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

紫外线辐射(UVR)在皮肤癌的发展中起着重要作用。我们之前曾报道过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)后容易患皮肤癌。DNA损伤会导致肿瘤抑制基因或癌基因的突变。肿瘤免疫对癌症的发展和生长非常重要。我们已经证明UVR和DMBA对XPA(-/-)小鼠的接触性超敏反应和肿瘤免疫有明显的抑制作用。移植的肿瘤细胞免疫排斥野生型小鼠和XPA(-/-)小鼠，除非暴露于UVB。另一方面，将肿瘤细胞注射到经UVB照射的XPA小鼠皮肤中，没有被排斥，并生长成一个大肿瘤。在本研究中，我们研究了与UVR诱导的免疫抑制有关的可溶性因子或细胞因子。中波紫外线或DMBA诱导的炎症和免疫抑制可被前列腺素合成抑制剂吲哚美辛预先处理。进一步证明紫外线和二甲基丁酸能显著刺激环氧合酶2、IL-10和肿瘤坏死因子α的表达，具有免疫抑制作用。这些结果表明，DNA损伤刺激免疫抑制因子的产生，损害肿瘤免疫。

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.