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IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide

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IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide Production, Oxidative DNA Damage, and Upregulation of Dual Oxidase 2 in Human Colon and Pancreatic This information is current as Cancer Cells of September 26, 2021. Yongzhong Wu, Mariam M. Konaté, Jiamo Lu, Hala Makhlouf, Rodrigo Chuaqui, Smitha Antony, Jennifer L. Meitzler, Michael J. Difilippantonio, Han Liu, Agnes Juhasz, Guojian Jiang, Iris Dahan, Krishnendu Roy and James H. Downloaded from Doroshow J Immunol published online 23 September 2019 http://www.jimmunol.org/content/early/2019/09/20/jimmun ol.1800469 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2019/09/20/jimmunol.180046 Material 9.DCSupplemental Why The JI? Submit online. by guest on September 26, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 23, 2019, doi:10.4049/jimmunol.1800469 The Journal of Immunology IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide Production, Oxidative DNA Damage, and Upregulation of Dual Oxidase 2 in Human Colon and Pancreatic Cancer Cells Yongzhong Wu,* Mariam M. Konate´,† Jiamo Lu,* Hala Makhlouf,† Rodrigo Chuaqui,† Smitha Antony,† Jennifer L. Meitzler,* Michael J. Difilippantonio,† Han Liu,† Agnes Juhasz,* Guojian Jiang,* Iris Dahan,† Krishnendu Roy,† and James H. Doroshow*,† Dual oxidase 2 (DUOX2) generates H2O2 that plays a critical role in both host defense and chronic inflammation. Previously, we demonstrated that the proinflammatory mediators IFN-g and LPS enhance expression of DUOX2 and its maturation factor DUOXA2 through STAT1- and NF-kB‒mediated signaling in human pancreatic cancer cells. Using a panel of colon and pancre- Downloaded from atic cancer cell lines, we now report the induction of DUOX2/DUOXA2 mRNA and protein expression by the TH2 cytokine IL-4. IL-4 activated STAT6 signaling that, when silenced, significantly decreased induction of DUOX2. Furthermore, the TH17 cytokine IL-17A combined synergistically with IL-4 to increase DUOX2 expression in both colon and pancreatic cancer cells mediated, at least in part, by signaling through NF-kB. The upregulation of DUOX2 was associated with a significant increase in the production of extracellular H2O2 and DNA damage—as indicated by the accumulation of 8-oxo-dG and gH2AX—which was suppressed by the NADPH oxidase inhibitor diphenylene iodonium and a DUOX2-specific small interfering RNA. The clinical relevance of these experiments is suggested by immunohistochemical, microarray, and quantitative RT-PCR studies of human colon and pancreatic http://www.jimmunol.org/ tumors demonstrating significantly higher DUOX2, IL-4R, and IL-17RA expression in tumors than in adjacent normal tissues; in pancreatic adenocarcinoma, increased DUOX2 expression is adversely associated with overall patient survival. These data suggest a functional association between DUOX2-mediated H2O2 production and induced DNA damage in gastrointestinal malignancies. The Journal of Immunology, 2019, 203: 000–000. ecent studies suggest that reactive oxygen species (ROS) of activation (7–9). DUOX2 is a membrane-localized glycopro- play an important role as mediators of inflammation- tein composed of six transmembrane helices bearing a cytosolic R related malignancies by enhancing tumor cell prolifera- C-terminal FAD/NADPH binding domain, two cytosolic EF-hands by guest on September 26, 2021 tion and angiogenesis (1–3). ROS are produced in human tumors for calcium binding, and an extracellular N-terminal peroxidase-like by a variety of mechanisms, including by members of the mi- domain. In the presence of its cognate maturation factor DUOXA2, tochondrial electron transport chain (4) and the NADPH oxidase these structural components regulate the transfer of electrons from (NOX) gene family (5, 6). NADPH to molecular oxygen to generate H2O2 (7, 10–12), which is The seven NOX family members share certain structural homol- important for the synthesis of thyroid hormone (13) and plays an ogies while retaining distinct tissue specificities and mechanisms important host defense role against pathogens in the airway and gastrointestinal mucosal epithelia (10, 14, 15). *Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Increasing evidence suggests an etiologic role for DUOX2 in Institute, National Institutes of Health, Bethesda, MD 20892; and †Division of Cancer gastrointestinal malignancies; it is overexpressed in premalignant Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 chronic inflammatory states of the colon (16, 17), adenomatous large intestinal polyps (18), and in chronic pancreatitis (19) as well as ORCIDs: 0000-0003-1393-0998 (H.M.); 0000-0002-4676-7034 (M.J.D.); 0000- 0003-0541-0714 (K.R.). early stages of pancreatic ductal adenocarcinoma (PDAC) (20). The Received for publication March 27, 2018. Accepted for publication August 27, 2019. proinflammatory microenvironment of these diseases, including This work was supported by the Division of Cancer Treatment and Diagnosis and the overexpression of TH17 and TH2 cytokines (IL-17A and IL-4/IL-13) Center for Cancer Research, National Cancer Institute, National Institutes of Health. and their corresponding receptors, has been demonstrated to sig- The content of this publication does not necessarily reflect the views or policies of the nificantly alter epithelial tumor cell proliferation, survival, and Department of Health and Human Services, nor does mention of trade names, com- mercial products, or organizations imply endorsement by the U.S. Government. metastatic potential (21–24). Furthermore, prior studies from our Address correspondence and reprint requests to Dr. James H. Doroshow, Division of group demonstrated that LPS and the TH1 cytokine IFN-g stimulate Cancer Treatment and Diagnosis, National Cancer Institute, Building 31, Room 3A- DUOX2 expression and activity in pancreatic cancer cells by acti- 44, 31 Center Drive, National Institutes of Health, Bethesda, MD 20892. E-mail vating signaling through NF-kB and STAT1 (19, 25, 26). address: [email protected] In the present work, we found significant upregulation of The online version of this article contains supplemental material. DUOX2 and DUOXA2 in surgically resected colon cancer spec- Abbreviations used in this article: DPI, diphenylene iodonium; gH2AX, histone H2AX phosphorylation at serine 139; IHC, immunohistochemical, immunohistochemistry; imens compared with adjacent normal colonic epithelium and NAC, N-acetyl- L-cysteine; NOX, NADPH oxidase; 8-oxo-dG, 8-oxo-7,8-dihydro- have shown that DUOX2 expression is significantly associated 29-deoxyguanosine; PDAC, pancreatic ductal adenocarcinoma; PEG-catalase, with poor prognosis in pancreatic cancer clinical samples from catalase/polyethylene glycol; ROS, reactive oxygen species; siRNA, small interfering RNA; TCGA, The Cancer Genome Atlas; WCE, whole-cell extract. The Cancer Genome Atlas (TCGA). To understand the potential This article is distributed under The American Association of Immunologists, Inc., role of DUOX2 in adenocarcinomas of the pancreas and colon, we Reuse Terms and Conditions for Author Choice articles. examined the mechanisms of proinflammatory cytokine-related www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800469 2 IL-4 AND IL-17A ENHANCE DUOX2-RELATED DNA DAMAGE ROS production by DUOX2 in human pancreatic and colonic tumors (31). RNA expression levels for 11 oxidases or related proteins cancer cells. We report in this study that IL-4—alone or in com- were expressed for the 23 colon adenocarcinoma samples relative to the bination with IL-17A—strongly induces DUOX2/DUOXA2 mRNA pool of five normal colon mucosae from noncancer patients (31). Unsu- pervised clustering analysis with BRB-ArrayTools (32) was used to gen- and DUOX protein expression, leading to significantly increased erate a heat map. extracellular H2O2 accumulation and ROS-related DNA dam- For other comparative analyses between normal and malignant tissues, age. DUOX2 upregulation by IL-4 occurred as a consequence of primary human colon and pancreatic cancers and adjacent nonmalignant STAT6 activation and translocation to the nucleus, suggesting a tissue samples were acquired from the National Cancer Institute–sponsored Cooperative Human Tissue Network (Eastern, Mid-Western, and Mid- role for STAT6 in the transcriptional regulation of DUOX2 fol- Atlantic Divisions) in compliance with the Office of Human Subjects lowing proinflammatory stimulation. Enhanced expression of Research at the National Institutes of Health, Bethesda, MD. Specimens DUOX2 by IL-17A appears to be a consequence of NF-kB– were selected without regard to age, race/ancestry, or sex and were ob- related signal transduction. These
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