Meeran Syed M, Mantena Sudheer K, Meleth Sreelatha, Elmets Craig A, Katiyar Santosh K
Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall 557, P.O. Box 202, Birmingham, AL 35294, USA.
Mol Cancer Ther. 2006 Apr;5(4):825-32. doi: 10.1158/1535-7163.MCT-06-0003.
Solar UV radiation-induced immunosuppression is a risk factor for nonmelanoma skin cancer. Interleukin (IL)-12 has been shown to possess antitumor activity and inhibit the immunosuppressive effects of UV radiation in mice. In this study, we generated IL-12 knockout (KO) mice on a C3H/HeN background to characterize the role of IL-12 in photocarcinogenesis. After exposure of the mice to UVB (180 mJ/cm2) radiation thrice a week for 35 weeks, the development of UV-induced tumors was more rapid and the tumor multiplicity and tumor size were significantly higher in IL-12 KO mice than their wild-type (WT) counterparts (P < 0.05-0.001). Moreover, the malignant transformation of UVB-induced papillomas to carcinomas was higher in IL-12 KO mice in terms of carcinoma incidence (55%, P < 0.001), carcinoma multiplicity (77%, P < 0.001), and carcinoma size (81%, P < 0.001). As IL-12 has the ability to repair UV-induced DNA damage, we determined this effect in our in vivo IL-12 KO mouse model. We found that UVB-induced DNA damage in the form of cyclobutane pyrimidine dimers was removed or repaired more rapidly in WT mice than IL-12 KO mice. Similarly, the UVB-induced sunburn cell formation is primarily a consequence of DNA damage. It was observed that UVB-induced sunburn cells were repaired rapidly in WT mice compared with IL-12 KO mice. The rapid removal or repair of UV-induced cyclobutane pyrimidine dimers or sunburn cells will result in reduced risk of photocarcinogenesis. Taken together, our data show that IL-12 deficiency is associated with the greater risk of photocarcinogenesis in mice, and this may be due to reduction in damaged DNA repair ability.
日光紫外线辐射引起的免疫抑制是非黑色素瘤皮肤癌的一个风险因素。白细胞介素（IL）-12已被证明具有抗肿瘤活性，并能抑制紫外线辐射对小鼠的免疫抑制作用。在本研究中，我们培育了C3H/HeN背景下的IL-12基因敲除（KO）小鼠，以确定IL-12在光致癌作用中的作用。将小鼠每周三次暴露于UVB（180 mJ/cm2）辐射下，持续35周，与野生型（WT）对照小鼠相比，IL-12 KO小鼠中紫外线诱导肿瘤的发生更为迅速，肿瘤数量和肿瘤大小显著更高（P < 0.05 - 0.001）。此外，就癌发病率（55%，P < 0.001）、癌数量（77%，P < 0.001）和癌大小（81%，P < 0.001）而言，IL-12 KO小鼠中UVB诱导的乳头状瘤向癌的恶性转化更高。由于IL-12具有修复紫外线诱导的DNA损伤的能力，我们在体内IL-12 KO小鼠模型中确定了这种作用。我们发现，与IL-12 KO小鼠相比，WT小鼠中以环丁烷嘧啶二聚体形式存在的UVB诱导的DNA损伤去除或修复得更快。同样，UVB诱导的晒伤细胞形成主要是DNA损伤的结果。据观察与IL-12 KO小鼠相比，WT小鼠中UVB诱导的晒伤细胞修复迅速。紫外线诱导的环丁烷嘧啶二聚体或晒伤细胞的快速去除或修复将降低光致癌风险。综上所述，我们的数据表明IL-12缺乏与小鼠光致癌风险增加有关，这可能是由于受损DNA修复能力降低所致。
