IFNgamma promotes papilloma development by up-regulating Th17-associated inflammation.
IFNgamma 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 IFNgamma influences 7,12-dimethylbenz(a)anthracene (DMBA)-induced and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced papilloma development. We found here that IFNgamma expression was markedly up-regulated shortly after DMBA/TPA application to the skin. Surprisingly, neutralizing IFNgamma activity in vivo did not increase but rather decreased tumor development. Furthermore, IFNgamma receptor-deficient mice were also more resistant to papilloma development than their counterparts were. IFNgamma 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 alpha, interleukin (IL)-6, and transforming growth factor beta was largely dependent on host IFNgamma 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 IFNgamma 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 IFNgamma, under certain conditions, may promote tumor development by enhancing a Th17-associated inflammatory reaction.
Xiao
Mingjie
M
National Laboratory of Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology.
Wang
Chunhui
C
Zhang
Jinhua
J
Li
Zhiguang
Z
Zhao
Xueqiang
X
Qin
Zhihai
Z
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D007249:Inflammation / Q000150:complications / Q000209:etiology*; D007371:Interferon-gamma / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology*; D051379:Mice; D010212:Papilloma / Q000209:etiology*; D010766:Phosphorylation; D017471:Receptors, Interferon / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology*; D013755:Tetradecanoylphorbol Acetate; D000096743:Interferon gamma Receptor
D015127:9,10-Dimethyl-1,2-benzanthracene; D007371:Interferon-gamma; D020381:Interleukin-17; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D013755:Tetradecanoylphorbol Acetate; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse