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

¹National Laboratory of Biomacromolecules, ²Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, and ³Graduate School of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

^* To whom correspondence should be addressed. E-mail: zhihai{at}ibp.ac.cn.

	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 , interleukin (IL)-6, and transforming growth factor 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 Res 2009;69(5):2010–7]

Key Words: IFN, Skin carcinogenesis, Papilloma, Th17, Inflammation

This article has been cited by other articles:

				L. Wang, T. Yi, M. Kortylewski, D. M. Pardoll, D. Zeng, and H. Yu IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway J. Exp. Med., July 6, 2009; 206(7): 1457 - 1464. [Abstract] [Full Text] [PDF]