Li Xiaolu, Eckard Jonathan, Shah Rajendra, Malluck Chenlu, Frenkel Krystyna
Department of Environmental Medicine, New York University School of Medicine, New York, New York 10016, USA.
Cancer Res. 2002 Jan 15;62(2):417-23.
Tumor-initiating properties of complete carcinogens such as 7,12-dimethylbenz(a)anthracene (DMBA) are well known but not the mechanism of DMBA-mediated tumor promotion. Our hypothesis is that interleukin (IL)-1alpha, an early proinflammatory cytokine that initiates a cascade of other cytokines and growth factors, is up-regulated by DMBA and contributes to inflammation and carcinogenesis. We found that topical exposure of SENCAR mice to a carcinogenic DMBA dose indeed triggers significant increases in mouse skin IL-1alpha and IL-1alpha mRNA. Five DMBA applications (200 nmol each) caused a statistically significant (P = 0.02) increase in serum IL-1alpha, comparable with that induced by 12-O-tetradecanoylphorbol-13-acetate, a potent tumor promoter. IL-1alpha increase in serum was evident 24 h after the first DMBA application, whereas that in skin required five DMBA doses and became statistically significant (P < 0.0003) 48 h later. Skin IL-1alpha enhancement was preceded by a 6-fold up-regulation of IL-1alpha mRNA. A pretreatment with antimurine IL-1alpha antibody (Ab) nearly abolished DMBA-induced IL-1alpha mRNA (P = 0.0001) in skin and substantially decreased IL-1alpha in serum. Infiltration of polymorphonuclear leukocytes into skin was elevated 6-fold (P = 0.002) and >10-fold (P = 0.001) 24 h and 48 h after the fifth DMBA exposure, respectively. A pretreatment with anti-IL-1alpha Ab decreased polymorphonuclear leukocyte infiltration by >65% (P < 0.02), which suggests that this process is at least 65% under IL-1alpha control. Anti-IL-1alpha antibodies had no effect on edema, thus dissociating the two inflammation markers. Injecting anti-IL-1alpha Ab before DMBA applications significantly (P < 0.04) decreased the volume of carcinomas (CAs) in comparison with CAs that arose in mouse skin injected with a nonspecific serum. These results prove that IL-1alpha is induced by a carcinogenic DMBA dose and contributes to DMBA-induced inflammation and volume of CAs, hallmarks of tumor promotion and progression.
诸如7,12 - 二甲基苯并(a)蒽（DMBA）等完全致癌物的肿瘤起始特性是众所周知的，但DMBA介导的肿瘤促进机制尚不清楚。我们的假设是，白细胞介素（IL）-1α作为一种早期促炎细胞因子，可引发一系列其他细胞因子和生长因子，它会被DMBA上调，并促进炎症和致癌作用。我们发现，将SENCAR小鼠局部暴露于致癌剂量的DMBA确实会引发小鼠皮肤中IL -1α和IL -1α mRNA的显著增加。五次涂抹DMBA（每次200 nmol）导致血清IL -1α出现具有统计学意义的增加（P = 0.02），与由强效肿瘤促进剂12 - O - 十四烷酰佛波醇 -13 - 乙酸酯诱导的增加相当。首次涂抹DMBA后24小时血清中IL -1α就明显增加，而皮肤中的增加则需要五次DMBA涂抹，48小时后具有统计学意义（P < 0.0003）。皮肤中IL -1α的增强之前是IL -1α mRNA上调6倍。用抗小鼠IL -1α抗体（Ab）预处理几乎消除了皮肤中DMBA诱导的IL -1α mRNA（P = 0.0001），并显著降低了血清中的IL -1α。在第五次暴露于DMBA后24小时和48小时，多形核白细胞向皮肤的浸润分别增加了6倍（P = 0.002）和>10倍（P = 0.001）。用抗IL -1α Ab预处理使多形核白细胞浸润减少>65%（P < 0.02），这表明该过程至少65%受IL -1α控制。抗IL -1α抗体对水肿没有影响，从而区分了这两种炎症标志物。与注射非特异性血清的小鼠皮肤中产生的癌相比，在涂抹DMBA之前注射抗IL -1α Ab显著（P < 0.04）降低了癌（CA）的体积。这些结果证明，致癌剂量的DMBA可诱导IL -1α，并促进DMBA诱导的炎症和癌的体积，这是肿瘤促进和进展的标志。
