Sharma Som D, Meeran Syed M, Katiyar Nandan, Tisdale George B, Yusuf Nabiha, Xu Hui, Elmets Craig A, Katiyar Santosh K
Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall 557, Birmingham, AL 35294, USA.
Carcinogenesis. 2009 Nov;30(11):1970-7. doi: 10.1093/carcin/bgp228. Epub 2009 Sep 16.
Interleukin (IL)-12 deficiency exacerbates tumorigenesis in ultraviolet (UV) radiation-induced skin. Here, we assessed the effects of IL-12 deficiency on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated mouse skin. Using this two-stage chemical carcinogenesis protocol, we found that the development of DMBA/TPA-induced skin tumors was diminished in IL-12p40-knockout mice than in their wild-type counterparts. At the termination of the experiment (at 24 weeks), the skin tumor incidence and tumor multiplicity were significantly lower (P < 0.005) in interleukin-12-knockout (IL-12 KO) mice than in their wild-type counterparts, as was the malignant transformation of DMBA/TPA-induced papillomas to carcinomas (P < 0.01). Analysis of samples collected at the termination of the experiments for biomarkers of inflammation by immunohistochemical analysis, western blotting, enzyme-linked immunosorbent assay and real-time polymerase chain reaction revealed significantly lower levels of cyclooxygenase-2 (COX-2), prostaglandin (PG) E(2), proliferating cell nuclear antigen, cyclin D1 and the proinflammatory cytokines (tumor necrosis factor-alpha, IL-1beta and IL-6) in the DMBA/TPA-treated tumors and tumor-uninvolved skin of IL-12 KO mice than the skin and tumors of DMBA/TPA-treated wild-type mice. Analysis of the skin 6 h after TPA treatment showed that the TPA-induced promotion of skin edema, inflammatory leukocyte infiltration, COX-2 expression and PGE(2) production was significantly lower in the skin of the IL-12-KO mice than their wild-type counterparts. These results indicate that DMBA/TPA-induced skin tumor development differs from UVB-induced skin tumor development in that endogenous IL-12 acts to inhibit UVB-induced skin tumor development and malignant progression of the skin tumors to carcinoma. In the case of DMBA/TPA-induced skin tumor development, the endogenous IL-12 modulates the tumor promoter stimulation of inflammatory responses.
白细胞介素（IL）-12缺乏会加剧紫外线（UV）辐射诱导的皮肤肿瘤发生。在此，我们评估了IL-12缺乏对12-O-十四烷酰佛波醇-13-乙酸酯（TPA）诱导的、由7,12-二甲基苯并(a)蒽（DMBA）启动的小鼠皮肤肿瘤促进作用的影响。使用这种两阶段化学致癌方案，我们发现与野生型对照相比，IL-12p40基因敲除小鼠中DMBA/TPA诱导的皮肤肿瘤的发生减少。在实验结束时（24周时），白细胞介素-12基因敲除（IL-12 KO）小鼠的皮肤肿瘤发生率和肿瘤多样性显著低于其野生型对照（P < 0.005），DMBA/TPA诱导的乳头瘤向癌的恶性转化情况也是如此（P < 0.01）。通过免疫组织化学分析、蛋白质印迹法、酶联免疫吸附测定和实时聚合酶链反应对实验结束时收集的样本进行炎症生物标志物分析，结果显示，与DMBA/TPA处理的野生型小鼠的皮肤和肿瘤相比，IL-12 KO小鼠经DMBA/TPA处理的肿瘤及未发生肿瘤的皮肤中，环氧合酶-2（COX-2）、前列腺素（PG）E2、增殖细胞核抗原、细胞周期蛋白D1和促炎细胞因子（肿瘤坏死因子-α、IL-1β和IL-6）的水平显著降低。对TPA处理6小时后的皮肤进行分析表明，与野生型对照相比，IL-12基因敲除小鼠皮肤中TPA诱导的皮肤水肿、炎性白细胞浸润、COX-2表达和PGE2产生的促进作用显著降低。这些结果表明，DMBA/TPA诱导的皮肤肿瘤发生与UVB诱导的皮肤肿瘤发生不同，内源性IL-12可抑制UVB诱导的皮肤肿瘤发生以及皮肤肿瘤向癌的恶性进展。就DMBA/TPA诱导的皮肤肿瘤发生而言，内源性IL-12可调节肿瘤促进剂对炎症反应的刺激。
