Details

Autor(en) / Beteiligte

• Wu, Yongzhong
• Konaté, Mariam M
• Lu, Jiamo
• Makhlouf, Hala
• Chuaqui, Rodrigo
• Antony, Smitha
• Meitzler, Jennifer L
• Difilippantonio, Michael J
• Liu, Han
• Juhasz, Agnes
• Jiang, Guojian
• Dahan, Iris
• Roy, Krishnendu
• Doroshow, James H

Titel

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

Ist Teil von

• The Journal of immunology (1950), 2019-11, Vol.203 (9), p.2532-2544

Ort / Verlag

United States: AAI

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Dual oxidase 2 (DUOX2) generates H O 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 T 2 cytokine IL-4. IL-4 activated STAT6 signaling that, when silenced, significantly decreased induction of DUOX2. Furthermore, the T 17 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 H O 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 H O production and induced DNA damage in gastrointestinal malignancies.