Interleukin-1 alpha Up-Regulation in Vivo by a Potent Carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and Control of DMBA-induced Inflammatory Responses

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)-1 alpha , 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-1 alpha and IL-1 alpha mRNA. Five DMBA applications (200 nmol each) caused a statistically significant (P = 0.02) increase in serum IL-1 alpha , comparable with that induced by 12-O-tetradecanoylphorbol-13-acetate, a potent tumor promoter. IL-1 alpha 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-1 alpha enhancement was preceded by a 6-fold up-regulation of IL-1 alpha mRNA. A pretreatment with antimurine IL-1 alpha antibody (Ab) nearly abolished DMBA-induced IL-1 alpha mRNA (P = 0.0001) in skin and substantially decreased IL-1 alpha 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-1 alpha Ab decreased polymorphonuclear leukocyte infiltration by >65% (P < 0.02), which suggests that this process is at least 65% under IL-1 alpha control. Anti-IL-1 alpha antibodies had no effect on edema, thus dissociating the two inflammation markers. Injecting anti-IL-1 alpha 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-1 alpha is induced by a carcinogenic DMBA dose and contributes to DMBA-induced inflammation and volume of CAs, hallmarks of tumor promotion and progression.