INTERLEUKIN-1-ALPHA GENE-EXPRESSION AND LOCALIZATION OF INTERLEUKIN-1-ALPHA PROTEIN DURING TUMOR PROMOTION

Treatment of the dorsal epidermis of SENCAR mice with 12-O-tetradecano ylphorbol-13-acetate (TPA) induced a time- and dose-dependent stimulat ion of interleukin-1alpha (IL-1alpha) gene expression. Levels of IL-1a lpha mRNA were elevated as early as 15 min and peaked at 3-4 h after a single application of TPA (2 mug or 10 mug). IL-1alpha gene expressio n increased in epidermal tissue isolated from SENCAR mice at 1, 3, 6, 10, 16, and 22 wk after a single treatment with 10 nmol 7,12-dimethylb enz[a]anthracene (DMBA) and subsequent twice-weekly application of 2 m ug TPA. IL-1alpha-immunoreactive protein was specifically localized wi thin suprabasal keratinocytes in cutaneous tissue isolated from mice t reated with DMBA-TPA for 1-22 wk and in nonproliferating cells located within papilloma tissue isolated from SENCAR mice at 22 wk after init iation and promotion. Basal cells within hyperplastic epidermis did no t produce IL-1alpha-immunoreactive protein. DMBA treatment alone did n ot induce IL-1alpha gene expression. Injection of IL-1alpha-specific a ntibodies (50 mug) into SENCAR mice via the tail vein 2 h before treat ment with TPA (2 mug or 10 mug) significantly (P < 0.05) inhibited the skin thickening usually observed 24 h after treatment with TPA. Autor adiography studies showed that injection of anti-IL-1alpha antibodies inhibited incorporation of [methyl-H-3]thymidine by keratinocytes with in the epidermis and by cells within hair follicles. It also inhibited neutrophil infiltration into the dermis, which usually results from t opical application of TPA. These data suggest that IL-1alpha is a pivo tal cytokine produced by specific subpopulations of epidermal keratino cytes and that IL-1alpha primarily regulates the epidermal proliferati ve response of a distinctly separate population of keratinocytes after topical exposure of murine epidermis to TPA and secondarily modulates neutrophil migration into the dermis. Consequently, manipulation of I L-1alpha may be a way to attenuate or abrogate the cutaneous response to TPA by altering keratinocyte proliferation, the resultant hyperplas ia, and a portion of the inflammatory response characterized by dermal infiltration of neutrophils. (C) 1993 Wiley-Liss, Inc.