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首页> 外文期刊>The Journal of Immunology: Official Journal of the American Association of Immunologists >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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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

机译：胰腺癌细胞株中IFN-γ和脂多糖协同诱导双重氧化酶2和双重氧化酶A2需要TLR4的激活

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摘要

Pancreatitis is associated with release of proinflammatory cytokines and reactive oxygen species and plays an important role in the development of pancreatic cancer. We recently demonstrated that dual oxidase (Duox)2, an NADPH oxidase essential for reactive oxygen species-related, gastrointestinal host defense, is regulated by IFN-γ-mediated Stat1 binding to the Duox2 promoter in pancreatic tumor lines. Because LPS enhances the development and invasiveness of pancreatic cancer in vivo following 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 small interfering RNAs, as well as 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 upregulation 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 prooxidant milieu that could increase the pathologic potential of pancreatic inflammation and pancreatic cancer cells.
机译：胰腺炎与促炎细胞因子和活性氧的释放有关，并且在胰腺癌的发展中起重要作用。我们最近证明，双重氧化酶（Duox）2，一种NADPH氧化酶，对于与活性氧相关的胃肠道宿主防御至关重要，是由IFN-γ介导的Stat1与胰腺肿瘤细胞中Duox2启动子的结合调节的。由于LPS在TLR4相关的NF-κB激活后增强了胰腺癌的体内发展和侵袭性，因此我们研究了单独或与IFN-γ结合使用LPS调节Duox2。我们发现，LPS增强了BxPC-3和CFPAC-1胰腺癌细胞中IFN-γ对TLR4的上调，从而导致NF-κB活化，NF-κB（p65）在细胞核中蓄积，并增加了TNF-α的结合。 p65对Duox2启动子。用小的干扰RNA以及两种独立的NF-κB抑制剂使TLR4沉默，减弱了BxPC-3细胞中LPS和IFN-γ介导的Duox2上调。 IFN-γ和LPS对Duox2表达的诱导可能是由Stat1的IFN-γ相关激活与NF-κB相关的Duox2上调共同作用引起的。通过同时暴露于LPS和IFN-γ产生的H2O2的持续胞外积累导致BxPC-3细胞增殖与G1细胞周期阻滞，细胞凋亡和DNA损伤相关的降低约50％。我们还证明了胰腺癌异种移植物中和慢性胰腺炎患者体内Duox表达的上调。这些结果表明，炎症细胞因子可以相互作用产生依赖于Duox的促氧化剂环境，这可能会增加胰腺炎症和胰腺癌细胞的病理学潜能。

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