IFNγ Promotes Papilloma Development by Up-regulating Th17-Associated Inflammation

Abstract

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.

Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

“…Suppressor of cytokine signaling-1 (SOCS1)-deficient mice spontaneously developed colorectal carcinomas in an IFNg-dependent manner (13). IFNg has been demonstrated to promote papilloma development (14). Mouse mammary adenocarcinomas transfected with the murine IFNg gene give rise to progressive tumors (15).…”

FSP1+ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation

“…23 The thickness of the epidermis (in micrometers) was measured with an image system (Photoshop; Adobe Systems Inc., San Jose, CA) and calculated as following: the actual thickness of epidermis ϭ on-screen measurements of epidermis/magnification (10 fields per section). For FSP1 staining, paraffin sections were incubated with rabbit anti-FSP1 polyclonal antibodies (a gift from Dr. Eric G. Neilson), then incubated with biotinylated secondary antibody followed by streptavidin-peroxidase.…”

IFN-γ–Mediated Downregulation of LXA4 Is Necessary for the Maintenance of Nonresolving Inflammation and Papilloma Persistence

“…Papillomas and local inflammation were induced as described before (20). In brief, an area of 200 mm 2 dorsal skin was shaved in every mouse and 25 mg DMBA (Sigma) in 100 mL acetone was administered to the shaved skin.…”

“…For neutralizing endogenous IFN-g, mice were injected with the rat anti-mouse IFN-g monoclonal antibody (mAb; R4-6A2; ref. 20) or with an isotype-matched control mAb [rat immunoglobulin G (IgG)] as control. Antibodies (0.3 mg per mouse) were administered once a week by intraperitoneal injection.…”

“…We previously showed that IFN-g promoted papilloma development via upregulation of local IL-17 and inflammatory response in the DMBA/TPA model (20). However, the role of IFN-g during inflammation resolution and spontaneous papilloma regression is still to be investigated.…”