Department of Immunology and the Center for Cancer Immunology Research, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.
J Invest Dermatol. 2010 May;130(5):1428-37. doi: 10.1038/jid.2009.329. Epub 2009 Oct 15.
UV exposure induces skin cancer, in part, by inducing immune suppression. Repairing DNA damage, neutralizing the activity of cis-urocanic acid, and reversing oxidative stress abrogate UV-induced immune suppression and skin cancer induction, suggesting that DNA, UCA, and lipid photo-oxidation serve as UV photoreceptors. What is not clear is whether signaling through each of these different photoreceptors activates independent pathways to induce biological effects or whether there is a common checkpoint where these pathways converge. Here, we show that agents known to reverse photocarcinogenesis and photoimmune suppression, such as platelet-activating factor (PAF) and serotonin (5-HT) receptor antagonists, regulate DNA repair. Pyrimidine dimer repair was accelerated in UV-irradiated mice injected with PAF and 5-HT receptor antagonists. Nucleotide excision repair (NER), as measured by unscheduled DNA synthesis, was accelerated by PAF and 5-HT receptor antagonists. Injecting PAF and 5-HT receptor antagonists into UV-irradiated Xeroderma pigmentosum complementation group A-deficient mice, which lack the enzymes responsible for NER, did not accelerate photoproduct repair. Similarly, UV-induced formation of 8-oxo-deoxyguanosine was reduced by PAF and 5-HT receptor antagonists. We conclude that PAF and 5-HT receptor antagonists accelerate DNA repair caused by UV radiation, which prevents immune suppression and interferes with photocarcinogenesis.
紫外线照射会导致皮肤癌，部分原因是它会引起免疫抑制。修复 DNA 损伤、中和顺式尿刊酸的活性以及逆转氧化应激可以消除 UV 诱导的免疫抑制和皮肤癌诱导，这表明 DNA、UCA 和脂质光氧化可作为 UV 光受体。目前尚不清楚的是，这些不同光受体中的每一个信号通路是否通过激活独立的途径来诱导生物学效应，或者这些途径是否存在一个共同的检查点，在这个检查点上它们汇聚在一起。在这里，我们表明，已知可逆转光致癌和光免疫抑制的药物，如血小板激活因子（PAF）和 5-羟色胺（5-HT）受体拮抗剂，可调节 DNA 修复。在注射了 PAF 和 5-HT 受体拮抗剂的紫外线照射的小鼠中，嘧啶二聚体修复得到了加速。通过非计划 DNA 合成来衡量的核苷酸切除修复（NER）也因 PAF 和 5-HT 受体拮抗剂而加速。将 PAF 和 5-HT 受体拮抗剂注入缺乏负责 NER 的酶的 Xeroderma pigmentosum 互补组 A 缺陷型小鼠中，这些酶会加速光产物修复。同样，紫外线诱导的 8-氧-脱氧鸟苷的形成也被 PAF 和 5-HT 受体拮抗剂减少。我们得出结论，PAF 和 5-HT 受体拮抗剂可加速由紫外线辐射引起的 DNA 修复，从而防止免疫抑制和干扰光致癌作用。
