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.

Abstract

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-γ and LPS enhance expression of DUOX2 and its maturation factor DUOXA2 through STAT1- and NF-κB‒mediated signaling in human pancreatic cancer cells. Using a panel of colon and pancreatic 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-κB. 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 γH2AX-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 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.

• Authors: 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, James H Doroshow
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 203 Issue 9 Pg. 2532-2544 (11 01 2019) ISSN: 1550-6606 [Electronic] United States
• PMID: 31548328 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• IL17A protein, human
• Interleukin-17
• NF-kappa B
• Receptors, Interleukin-4
• STAT6 Transcription Factor
• STAT6 protein, human
• Interleukin-4
• Hydrogen Peroxide
• Dual Oxidases
• DUOX2 protein, human

Topics

• Cell Line, Tumor
• Colonic Neoplasms (metabolism, pathology)
• DNA Damage
• Dual Oxidases (genetics)
• Humans
• Hydrogen Peroxide (metabolism)
• Interleukin-17 (pharmacology)
• Interleukin-4 (pharmacology)
• NF-kappa B (physiology)
• Oxidation-Reduction
• Pancreatic Neoplasms (metabolism, pathology)
• Receptors, Interleukin-4 (physiology)
• STAT6 Transcription Factor (physiology)
• Signal Transduction
• Up-Regulation