IFN; plays a crucial role in immunity against a variety of transplanted tumors and methylcholanthrene-mediated tumorigenesis in mice. However, it is not clear whether and how endogenous IFN; influences 7,12-dimethylbenz(a)anthracene (DMBA)-induced and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma development. We found here that IFN; expression was markedly up-regulated shortly after DMBA/TPA application to the skin. Surprisingly, neutralizing IFN; activity in vivo did not increase but rather decreased tumor development. Furthermore, IFN; receptor-deficient mice were also more resistant to papilloma development than their counterparts were. IFN; acted mainly in the promotion stage of papilloma development by enhancing TPA-induced leukocyte infiltration and epidermal hyperproliferation. The up-regulation of tumor necrosis factor A, interleukin (IL)-6, and transforming growth factor B was largely dependent on host IFN; responsiveness. Remarkably, up-regulation of both IL-17 expression in the skin and T helper 17 (Th17) cell number in draining lymph nodes after DMBA/TPA treatment was dependent on IFN; signaling. Depletion of IL-17 not only decreased the DMBA/TPA-induced inflammation and keratinocyte proliferation but also delayed papilloma development. These results show that IFN;, under certain conditions, may promote tumor development by enhancing a Th17-associated inflammatory reaction.

Cancer development is often associated with increased fibroblast proliferation and extensive fibrosis; however, the role of fibroblasts during carcinogenesis remains largely unknown. Using the 7,12-dimethylbenz-(a)anthracene and 12-O-tetradecanoylphorbol-13-acetateinduced two-stage skin carcinogenesis model, we demonstrated here that there was a massive accumulation and proliferation of fibroblasts in the skin shortly after application of carcinogen. Selective abatement of these cells during the promotion stage drastically decreased incidence and progression of papillomas. This correlated well with reduced macrophage infiltration and impaired cytokine storm in the affected skin. 12-O-tetradecanoylphorbol-13-acetate stimulated skin fibroblasts, secreting high levels of monocyte chemotactic protein-1, and neutralization of this chemokine eliminated almost completely the fibroblast-induced chemotaxis of macrophages. These results strongly suggest that fibroblasts promote skin tumor development by producing monocyte chemotactic protein-1 and maintaining chronic inflammation.