PO.IM02.03 · 免疫学
白细胞介素-1以STAT1/STAT3依赖方式上调人胰腺癌细胞中双氧化酶2的表达和ROS生成
Interleukin-1 upregulates dual oxidase 2 expression and ROS production in human pancreatic cancer cells in a STAT1/STAT3-dependent manner
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摘要 Abstract
中文摘要
慢性胰腺炎和持续性胰腺炎症增加胰腺导管腺癌（PDAC）的风险，部分是通过释放促炎细胞因子和过量生成活性氧（ROS）。白细胞介素-1（IL-1）是一种由恶性细胞或微环境细胞分泌的主要上游细胞因子，可促进胰腺炎症、肿瘤发生、侵袭性和瘤内异质性。此前，我们实验室已确立双氧化酶2（DUOX2）——七个NADPH氧化酶（NOX）家族成员之一——在H2O2介导的宿主防御和胃肠道慢性炎症中发挥关键作用。在多种人胰腺癌细胞系中，暴露于包括IFN-gamma、IL-4和IL-17A在内的各种促炎细胞因子后，DUOX2与其成熟因子DUOXA2一起上调并表达。在本研究中，我们发现IL-1alpha和IL-1beta在一组人PDAC细胞系和患者来源的PDAC类器官中强力上调DUOX2/DUOXA2的mRNA和蛋白表达。IL-1暴露触发STAT1和STAT3的瞬时激活，随后是DUOX2/DUOXA2的持续诱导，而不增加其他NOX家族成员的表达。PDAC细胞系中经典IL-1信号的激活得到以下观察结果的支持：在IL-1处理的PDAC细胞中，IL-1相关的IL-8（CXCL8）mRNA上调，CXCL8是一种对中性粒细胞募集必需的趋化因子和血管生成的强效促进剂。共同给予Anakinra（一种IL-1受体拮抗剂）在体外显著抑制IL-1诱导的DUOX2/DUOXA2和CXCL8表达。在BxPC-3细胞中敲除DUOX2确立了DUOX2是IL-1介导的ROS生成的主要来源。对近端IL-1通路节点（如IL-1R1、MYD88和IRAK1/2）的靶向siRNA敲低显著降低了DUOX2/DUOXA2和CXCL8的表达。我们还发现，STAT1和STAT3这两个参与IL-1通路下游转录的转录因子，对胰腺癌中DUOX2/DUOXA2的调控至关重要。总之，这些发现定义了一个IL-1-STAT1/STAT3轴，驱动PDAC中DUOX2依赖性的ROS生成，强化了促氧化、促炎的微环境。
查看英文原文 English abstract
Chronic pancreatitis and sustained pancreatic inflammation increase the risk of pancreatic ductal adenocarcinoma (PDAC), in part through the release of pro-inflammatory cytokines and excessive generation of reactive oxygen species (ROS). Interleukin-1 (IL-1), a major upstream cytokine secreted by malignant or microenvironmental cells, promotes pancreatic inflammation, tumorigenesis, invasiveness, and intratumoral heterogeneity. Previously, our laboratory has established that dual oxidase 2 (DUOX2), one of seven NADPH oxidase (NOX) family members, plays a critical role in H2O2-mediated host defense and chronic inflammation in the gastrointestinal tract. DUOX2 is upregulated and expressed along with its maturation factor, DUOXA2, in several human pancreatic cancer cell lines following exposure to various pro-inflammatory cytokines, including IFN-gamma, IL-4, and IL-17A. In the present study, we show that IL-1alpha and IL-1beta robustly upregulate DUOX2/DUOXA2 mRNA and protein expression in a panel of human PDAC cell lines and patient-derived PDAC organoids. IL-1 exposure triggers transient activation of STAT1 and STAT3, followed by sustained induction of DUOX2/DUOXA2, without increasing expression of other NOX family members. Activation of canonical IL-1 signaling in PDAC cell lines was supported by the observation of IL-1-related upregulation of IL-8 (CXCL8) mRNA, a chemokine essential for neutrophil recruitment and a potent promoter of angiogenesis, in IL-1-treated PDAC cells. Co-administration of Anakinra, an IL-1 receptor antagonist, markedly suppresses IL-1-induced DUOX2/DUOXA2 and CXCL8 expression in vitro . Knocking out DUOX2 in BxPC-3 cells established DUOX2 as the predominant source of IL-1-mediated ROS production. Targeted siRNA knockdown of proximal IL-1 pathway nodes, such as IL-1R1, MYD88 and IRAK1/2, significantly decreased expression of DUOX2/DUOXA2 and of CXCL8. We also found that STAT1 and STAT3, two transcription factors involved in downstream transcription in the IL-1 pathway, are crucial for the regulation of DUOX2/DUOXA2 in pancreatic cancer. Collectively, these findings define an IL-1-STAT1/STAT3 axis that drives DUOX2-dependent ROS production in PDAC, reinforcing a pro-oxidant, pro-inflammatory microenvironment.
利益披露 Disclosure
D. J. Mallick, None..
Y. Wu, None..
M. M. Konaté, None..
B. A. Diebold, None..
S. Antony, None..
J. L. Meitzler, None..
G. Jiang, None..
J. Lu, None..
K. K. Roy, None.