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-tetradecanoylphorbol-13-acetate (TPA) induced a time- and dose-dependent stimulation of interleukin-1alpha (IL-1alpha) gene expression. Levels of IL-1alpha 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 expression 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-dimethylbenz[a]anthracene (DMBA) and subsequent twice-weekly application of 2 mug TPA. IL-1alpha-immunoreactive protein was specifically localized within suprabasal keratinocytes in cutaneous tissue isolated from mice treated with DMBA-TPA for 1-22 wk and in nonproliferating cells located within papilloma tissue isolated from SENCAR mice at 22 wk after initiation and promotion. Basal cells within hyperplastic epidermis did not produce IL-1alpha-immunoreactive protein. DMBA treatment alone did not induce IL-1alpha gene expression. Injection of IL-1alpha-specific antibodies (50 mug) into SENCAR mice via the tail vein 2 h before treatment with TPA (2 mug or 10 mug) significantly (P < 0.05) inhibited the skin thickening usually observed 24 h after treatment with TPA. Autoradiography studies showed that injection of anti-IL-1alpha antibodies inhibited incorporation of [methyl-H-3]thymidine by keratinocytes within the epidermis and by cells within hair follicles. It also inhibited neutrophil infiltration into the dermis, which usually results from topical application of TPA. These data suggest that IL-1alpha is a pivotal cytokine produced by specific subpopulations of epidermal keratinocytes and that IL-1alpha primarily regulates the epidermal proliferative 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 IL-1alpha may be a way to attenuate or abrogate the cutaneous response to TPA by altering keratinocyte proliferation, the resultant hyperplasia, and a portion of the inflammatory response characterized by dermal infiltration of neutrophils. (C) 1993 Wiley-Liss, Inc.