NDLI: Activation of Toll-Like Receptor 4 Is Required for the Synergistic Induction of Dual Oxidase 2 and Dual Oxidase A2 by Interferon-γ and Lipopolysaccharide in Human Pancreatic Cancer Cell Lines§

Content Provider	PubMed Central
Author	Wu, Yongzhong Lu, Jiamo Antony, Smitha Juhasz, Agnes Liu, Han Jiang, Guojian Meitzler, Jennifer L. Hollingshead, Melinda Haines, Diana C. Butcher, Donna Roy, Krishnendu Doroshow, James H.
Abstract	Pancreatitis is associated with release of pro-inflammatory cytokines and reactive oxygen species and plays an important role in the development of pancreatic cancer. We recently demonstrated that dual oxidase 2 (Duox2), an NADPH oxidase essential for ROS-related, gastrointestinal host defense, is regulated by IFN-γ-mediated Stat1 binding to the Duox2 promoter in pancreatic tumor lines. Because lipopolysaccharide (LPS) enhances the development and invasiveness of pancreatic cancer in vivo following Toll-like receptor 4 (TLR4)-related activation of NF-κB, we examined whether LPS, alone or combined with IFN-γ, regulated Duox2. We found that upregulation of TLR4 by IFN-γ in BxPC-3 and CFPAC-1 pancreatic cancer cells was augmented by LPS, resulting in activation of NF-κB, accumulation of NF-κB (p65) in the nucleus, and increased binding of p65 to the Duox2 promoter. TLR4 silencing with siRNAs, and two independent NF-κB inhibitors, attenuated LPS- and IFN-γ–mediated Duox2 upregulation in BxPC-3 cells. Induction of Duox2 expression by IFN-γ and LPS may result from IFN-γ-related activation of Stat1, acting in concert with NF-κB-related upregulation of Duox2. Sustained extracellular accumulation of H2O2 generated by exposure to both LPS and IFN-γ was responsible for an ≈ 50% decrease in BxPC-3 cell proliferation associated with a G1 cell cycle block, apoptosis, and DNA damage. We also demonstrated up-regulation of Duox expression in vivo, in pancreatic cancer xenografts and in patients with chronic pancreatitis. These results suggest that inflammatory cytokines can interact to produce a Duox-dependent pro-oxidant milieu that could increase the pathologic potential of pancreatic inflammation and pancreatic cancer cells.
Related Links	http://dx.doi.org/10.4049/jimmunol.1201725
Ending Page	1872
Page Count	14
Starting Page	1859
File Format	PDF
ISSN	00221767
e-ISSN	15506606
Journal	Journal of immunology (Baltimore, Md. : 1950)
Issue Number	4
Volume Number	190
Language	English
Publisher Date	2013-02-15
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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Activation of Toll-Like Receptor 4 Is Required for the Synergistic Induction of Dual Oxidase 2 and Dual Oxidase A2 by Interferon-γ and Lipopolysaccharide in Human Pancreatic Cancer Cell $Lines^{§}$

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