Chronic stress and susceptibility to skin cancer
Chronic stress and susceptibility to skin cancer
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DOI：
10.1093/jnci/dji401
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发表时间：
2005-12-07
影响因子：
10.3
通讯作者：
Dhabhar, FS
中科院分区：
文献类型：
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作者：
Saul, AN;Oberyszyn, TM;Dhabhar, FS
背景研究表明，慢性压力或紫外线辐射独立地抑制免疫力。鉴于其日益普遍，重要的是要了解慢性压力和紫外线辐射是否以及如何共同作用，以增加对疾病的易感性。因此，我们研究了压力诱导的UV诱导的鳞状细胞癌的出现和进展的增加的潜在介质。研究方法：对UV诱导肿瘤敏感的SKH 1小鼠未暴露于2240 J/m2的UVB辐射（未暴露，n = 4）或暴露于2240 J/m2的UVB辐射（n = 16），每周三次，持续10周。一半暴露于UVB的小鼠不受压力（即，它们留在它们的家笼中）而另一半长期处于应激状态（即，第4-6周期间限制）。从第11周至第34周每周测量UV诱导的肿瘤，在第34周收集血液，并在第35周收集组织。使用实时聚合酶链反应定量背部皮肤中白细胞介素（IL）-12p40、干扰素（IFN）-γ、IL-4、IL-10、CD 3 β和皮肤T细胞归巢趋化因子CCL 27/CTACK的mRNA表达。采用免疫组化和流式细胞术计数CD 4（+）、CD 8（+）和CD 25（+）白细胞。所有统计检验均为双侧检验。结果如下：应激小鼠的首次肿瘤中位时间较短（15周vs 16.5周，差异= 1.5周，95%置信区间[CI] = -3.0至3.3周; P = 0.03），并且比对照组早达到50%的发病率（15周vs 21周）。应激小鼠的IFN-γ水平也较低（平均值= 0.03与平均值= 0.07，差异= 0.04，95% CI = 0.004至0.073; P = 0.02），CCL 27/CTACK（平均值= 10 1 vs平均值= 142，差异= 41，95% CI = 8.1至74.4; P = 0.03），CD 3 + T细胞亚群（CD 3 + T细胞亚群）（均数= 0.18 vs均数= 0.36，差异= 0.18，95% CI = 0.06 ~ 0.30; P =.007）基因表达和浸润CD 4（+）细胞数量减少（平均值= 9.40对平均值= 13.7，差异= 4.3，95% CI = 2.36至6.32; P = 0.008）。此外，与非应激小鼠相比，应激小鼠有更多的调节/抑制性CD 25（+）细胞浸润肿瘤，循环中有更多的CD 4（+）CD 25（+）细胞（平均值= 0.36 vs平均值= 0.17，差异= 0.19，95% CI = 0.005至0.38; P = 0.03）。结论：慢性应激通过抑制1型细胞因子和保护性T细胞以及增加调节性/抑制性T细胞数量，增加了该小鼠模型对紫外线诱导的鳞状细胞癌的易感性。
Background. Studies have shown that chronic stress or UV radiation independently suppress immunity. Given their increasing prevalence, it is important to understand whether and how chronic stress and UV radiation may act together to increase susceptibility to disease. Therefore, we investigated potential mediators of a stress-induced increase in emergence and progression of UV-induced squamous cell carcinoma. Methods: SKH1 mice susceptible to UV-induced tumors were unexposed (naive, n = 4) or exposed (n = 16) to 2240 J/m(2) of UVB radiation three times a week for 10 weeks. Half of the UVB-exposed mice were left nonstressed (i.e., they remained in their home cages) and the other half were chronically stressed (i.e., restrained during weeks 4-6). UV-induced tumors were measured weekly from week 11 through week 34, blood was collected at week 34, and tissues were collected at week 35. mRNA expression of interleukin (IL)-12p40, interferon (IFN)-gamma, IL-4, IL-10, CD3 epsilon, and CCL27/CTACK, the skin T cell-homing chemokine, in dorsal skin was quantified using real-time polymerase chain reaction. CD4(+), CD8(+), and CD25(+) leukocytes were counted using immunohistochemistry and flow cytometry. All statistical tests were two-sided. Results: Stressed mice had a shorter median time to first tumor (15 versus 16.5 weeks, difference = 1.5 weeks, 95% confidence interval [CI] = -3.0 to 3.3 weeks; P =.03) and reached 50% incidence earlier than controls (15 weeks versus 21 weeks). Stressed mice also had lower IFN-gamma (mean = 0.03 versus mean = 0.07, difference = 0.04, 95% CI = 0.004 to 0.073; P =.02), CCL27/CTACK (mean = 10 1 versus mean = 142, difference = 41, 95% CI = 8.1 to 74.4; P =.03), and CD3 epsilon (mean = 0.18 versus mean = 0.36, difference = 0.18, 95% CI = 0.06 to 0.30; P =.007) gene expression and lower numbers of infiltrating CD4(+) cells (mean = 9.40 versus mean = 13.7, difference = 4.3, 95% CI = 2.36 to 6.32; P =.008) than nonstressed mice. In addition, stressed mice had more regulatory/suppressor CD25(+) cells infiltrating tumors and more CD4(+)CD25(+) cells in circulation (mean = 0.36 versus mean = 0.17, difference = 0.19, 95% CI = 0.005 to 0.38; P =.03) than nonstressed mice. Conclusions: Chronic stress increased susceptibility to UV-induced squamous cell carcinoma in this mouse model by suppressing type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell numbers.