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Keywords:

  • Tumor promotion;
  • phorbol esters;
  • interleukin-1;
  • antitumor promoters

Abstract

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-1α and whether phorbol ester—induced IL-1α expression can be blocked by antitumor promoters. Northern analysis of mRNA isolated from the dorsal skins of SENCAR mice treated with 1 μg of 4β-12-O-tetradecanoylphorbol-13-acetate (TPA) showed that a single application of TPA produced a significant increase in IL-1α 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-1α mRNA as one treatment. Of the other promoters tested, anthralin (22.6 μg), mezerein (2 μg), calcium ionophore A23187 (120 μg), and benzoyl peroxide (20 mg) induced IL-1α mRNA with different kinetics and to different extents. On the other hand, the non-tumor promoting phorbol ester analogue 4α-12-O-tetradecanoylphorbol-13-acetate had little effect on the expression of IL-1α mRNA. The effects of various antitumor promoters on TPA-induced IL-1α 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-1α mRNA expression; respectively. Therefore, this study suggests a possible role of IL-1α in the promotion stage of skin carcinogenesis.