Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.

Abstract	Cells undergoing xenobiotic or oxidative stress activate the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2), which initiates an intrinsic "stress surveillance" pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d(-/-) mice experienced a higher incidence of tumors and exacerbated viral infections compared to wild-type (WT) animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection.
Authors	Robert Saddawi-Konefka, Ruth Seelige, Emilie T E Gross, Eric Levy, Stephen C Searles, Allen Washington Jr, Endi K Santosa, Beichen Liu, Timothy E O'Sullivan, Olivier Harismendy, Jack D Bui
Journal	Cell reports (Cell Rep) Vol. 16 Issue 9 Pg. 2348-58 (08 30 2016) ISSN: 2211-1247 [Electronic] United States
PMID	27545889 (Publication Type: Journal Article)
Copyright	Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
Chemical References	Carcinogens IL17D protein, human Interleukin-17 NF-E2-Related Factor 2 NFE2L2 protein, human Methylcholanthrene
Topics	Animals Carcinogens Cell Line, Tumor Chlorocebus aethiops Gene Expression Regulation Humans Immunologic Surveillance Interleukin-17 (genetics, immunology) Methylcholanthrene Mice Mice, Inbred C57BL Mice, Knockout Muromegalovirus (growth & development, immunology) NF-E2-Related Factor 2 (genetics, immunology) Sarcoma (chemically induced, genetics, immunology, pathology) Signal Transduction Soft Tissue Neoplasms (chemically induced, genetics, immunology, pathology) Vaccinia virus (growth & development, immunology) Vero Cells

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