MODULATION OF INTERLEUKIN-1-ALPHA MESSENGER-RNA EXPRESSION IN MOUSE EPIDERMIS BY TUMOR PROMOTERS AND ANTAGONISTS

Increased expression of interleukin-1 (IL-1) in skin elicits a variety of responses, including inflammation and epidermal hyperplasia, which are also characteristic events elicited by tumor promoters. The goal of this study was to investigate whether various classes of tumor promoters increase expression of IL-1alpha and whether phorbol ester-induced IL-1alpha expression can be blocked by antitumor promoters. Northern analysis of mRNA isolated from the dorsal skins of SENCAR mice treated with 1 mug of 4beta-12-O-tetradecanoylphorbol-13-acetate (TPA) showed that a single application of TPA produced a significant increase in IL-1alpha mRNA at 6 h that decreased by 24 h after treatment. Two treatments of TPA at 48-h intervals induced, at 6 h, twice as much IL-1alpha mRNA as one treatment. Of the other promoters tested, anthralin (22.6 mug), mezerein (2 mug), calcium ionophore A23187 (120 mug), and benzoyl peroxide (20 mg) induced IL-1alpha mRNA with different kinetics and to different extents. On the other hand, the non-tumor promoting phorbol ester analogue 4alpha-12-O-tetradecanoylphorbol-1 3-acetate had little effect on the expression of IL-1alpha. mRNA. The effects of various antitumor promoters on TPA-induced IL-1alpha mRNA expression were also assessed. Fluocinolone acetonide, mepacrine, and 5,8,11,14-eicosatetraynoic acid were the most effective inhibitors, and each produced about 80% inhibition. Other antitumor promoters such as retinoic acid, N-tosyl-L-phenylalanine chloromethyl ketone, and butylated hydroxytoluene inhibited approximately 35%, 65%, and 50% of TPA-induced IL-1alpha mRNA expression, respectively. Therefore, this study suggests a possible role of IL-1alpha in the promotion stage of skin carcinogenesis.