Activation of TLR4 is required for the synergistic induction of dual oxidase 2 and dual oxidase A2 by IFN-γ and lipopolysaccharide in human pancreatic cancer cell lines.
Activation of TLR4 is required for the synergistic induction of dual oxidase 2 and dual oxidase A2 by IFN-γ and lipopolysaccharide in human pancreatic cancer cell lines.
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DOI：
10.4049/jimmunol.1201725
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发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Doroshow JH
中科院分区：
文献类型：
--
作者：
Wu Y;Lu J;Antony S;Juhasz A;Liu H;Jiang G;Meitzler JL;Hollingshead M;Haines DC;Butcher D;Roy K;Doroshow JH
胰腺炎与促炎细胞因子和活性氧的释放有关，在胰腺癌的发展中起重要作用。我们最近证明，双氧化酶2（Duox 2），一种NADPH氧化酶的ROS相关的，胃肠道宿主防御必不可少的，是由IFN-γ介导的Stat 1结合到Duox 2启动子在胰腺肿瘤细胞系的调节。由于脂多糖（LPS）在体内Toll样受体4（TLR 4）相关的NF-κB活化后增强胰腺癌的发展和侵袭性，我们检测了LPS单独或与IFN-γ联合是否调节Duox 2。我们发现，在BxPC-3和CFPAC-1胰腺癌细胞中，IFN-γ上调TLR 4可被LPS增强，导致NF-κB活化，NF-κB（p65）在细胞核中积聚，并增加p65与Duox 2启动子的结合。siRNA沉默TLR 4和两种独立的NF-κB抑制剂减弱了LPS和IFN-γ介导的BxPC-3细胞中Duox 2上调。IFN-γ和LPS诱导Duox 2表达可能是由于IFN-γ相关的Stat 1激活，与NF-κ B相关的Duox 2上调一致。通过暴露于LPS和IFN-γ产生的H2 O2的持续细胞外积累导致BxPC-3细胞增殖减少约50%，与G1细胞周期阻滞、凋亡和DNA损伤相关。我们还证实了Duox在体内、胰腺癌异种移植物和慢性胰腺炎患者中的表达上调。这些结果表明，炎症细胞因子可以相互作用，产生Duox依赖性促氧化环境，这可能会增加胰腺炎症和胰腺癌细胞的病理潜力。
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.
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