The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists
The environmental stressor ultraviolet B radiation inhibits murine antitumor immunity through its ability to generate platelet-activating factor agonists
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DOI：
10.1093/carcin/bgs152
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发表时间：
2012-07-01
期刊：
影响因子：
4.7
通讯作者：
Travers, Jeffrey B.
中科院分区：
文献类型：
--
作者：
Sahu, Ravi P.;Turner, Matthew J.;Travers, Jeffrey B.
对人或小鼠皮肤的普遍存在的促氧化应激因子紫外线B辐射（UVB）产生血小板活化因子（PAF）和具有PAF受体（PAF-R）激动活性的新型氧化修饰的甘油磷酸胆碱（Ox-GPCs）。这些脂质在涉及IL-10的过程中介导全身性免疫抑制。目前的研究试图确定UVB介导的系统性免疫抑制在小鼠黑色素瘤模型中的功能意义。我们表明，UVB照射可促进B16 F10肿瘤生长，并且依赖于宿主，但不依赖于黑色素瘤细胞;作为UVB或PAF-R激动剂氨甲酰基PAF（CPAF）的PAF-R表达均促进野生型（WT）小鼠中B16 F10肿瘤的生长，与B16 F10细胞是否表达PAF-Rs无关，但不会促进Pafr -/-小鼠中的肿瘤生长。UVB介导的实验小鼠肿瘤生长的增强被抗氧化剂抑制，证明了非酶促产生的Ox-GPC PAF-R激动剂的重要性。需要宿主免疫细胞作为CPAF诱导的肿瘤生长的增强，这在免疫缺陷NOD SCID小鼠中未观察到。最后，在WT小鼠中消耗针对IL-10的抗体或在FoxP 3（EGFP）转基因小鼠中消耗CD 25阳性细胞阻断UVB和/或CPAF诱导的肿瘤生长，支持在该过程中需要IL-10和TGFAP。这些发现表明，UVB产生的具有PAF-R激动活性的Ox-GPCs通过靶向宿主免疫细胞（最明显的是TGFs）介导全身免疫抑制来增强实验性鼠黑素瘤肿瘤生长。
Ubiquitous pro-oxidative stressor ultraviolet B radiation (UVB) to human or mouse skin generates platelet-activating factor (PAF) and novel oxidatively modified glycerophosphocholines (Ox-GPCs) with PAF-receptor (PAF-R) agonistic activity. These lipids mediate systemic immunosuppression in a process involving IL-10. The current studies sought to determine the functional significance of UVB-mediated systemic immunosuppression in an established model of murine melanoma. We show that UVB irradiation augments B16F10 tumor growth and is dependent on host, but not melanoma cell; PAF-R-expression as UVB or the PAF-R agonist, carbamoyl PAF (CPAF), both promote B16F10 tumor growth in wild-type (WT) mice, independent of whether B16F10 cells express PAF-Rs, but do not augment tumor growth in Pafr -/- mice. UVB-mediated augmentation of experimental murine tumor growth was inhibited with antioxidants, demonstrating the importance of Ox-GPC PAF-R agonists produced non-enzymatically. Host immune cells are required as CPAF-induced augmentation of tumor growth which is not seen in immunodeficient NOD SCID mice. Finally, depleting antibodies against IL-10 in WT mice or depletion of CD25-positive cells in FoxP3(EGFP) transgenic mice block UVB and/or CPAF-induced tumor growth supporting a requirement for IL-10 and Tregs in this process. These findings indicate that UVB-generated Ox-GPCs with PAF-R agonistic activity enhance experimental murine melanoma tumor growth through targeting host immune cells, most notably Tregs, to mediate systemic immunosuppression.