Induction of interleukin-6 in the epidermis of mice in response to tumor-promoting agents.

Recent reports imply that several epidermal cytokines have a functional role in the tumor promotion stage of the multistage carcinogenesis model in mouse dorsal skin. In this report we describe studies to assess the role of interleukin-6 (IL-6) in tumor promotion. Promoting, as well as non-promoting, hyperplastic agents were found to induce IL-6, as measured by mRNA expression. Inhibitors of tumor promotion inhibited tumor-promoter-mediated IL-6 induction. However, when mice were injected with a neutralizing antibody specific to murine IL-6, there was no effect on tumor-promoter-mediated epidermal hyperplasia and dermal inflammation. These studies suggest that even though IL-6 is produced in the epidermis following tumor promoter application, it does not modulate epidermal hyperplasia and dermal inflammation. Our findings also stress the importance of assessing, in in vivo studies, the function of those cytokines suggested by in vitro experiments to have important roles in tumor promotion.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in mouse skin in response to tumor-promoting agents and modulates dermal inflammation and epidermal dark cell numbers.

In mouse dorsal skin multistage carcinogenesis models, tumor promotion can be mediated by chemical agents, but also by wounding or abrasion of the epidermis, suggesting that endogenous growth factors mediate this process. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one such factor that has been reported to be produced by keratinocytes in vitro, and has been suggested both to stimulate keratinocyte proliferation, and also to be a chemoattractant for neutrophils and macrophages. In this study we examined the expression and function of GM-CSF in mouse skin following the application of tumor-promoting agents. Both single and multiple applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in accumulation of GM-CSF mRNA in the epidermis. Various phorbol and non-phorbol ester tumor promoters were found to induce increases in epidermal GM-CSF mRNA levels commensurate with their relative tumor promoting capabilities. Fluocinolone acetonide (FA) and tosyl phenylalanine chloromethyl ketone (TPCK), inhibitors of tumor promotion, inhibited tumor promoter-mediated GM-CSF accumulation, whereas all-trans-retinoic acid (RA) enhanced the TPA-induced increase. The retinoic acid analogue RO-109359 which, unlike RA, does not have tumor promoting activity per se, inhibited the TPA-induced increase in epidermal GM-CSF mRNA levels. When an antibody specific to GM-CSF was administered prior to TPA, the promoter-induced dermal inflammation and increase in epidermal dark cell number were reduced, yet promoter-induced epidermal hyperplasia was not. These findings implied that elevation of GM-CSF levels plays an important role in chemically-mediated mouse skin tumor promotion and principally via effects on promoter-induced inflammation and increased epidermal dark cell number.