CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings
CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings
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CPT-11 通过 JNK 和 NF-kappaB 信号传导激活 NLRP3 炎症小体。
DOI：
10.1016/j.taap.2015.09.025
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发表时间：
2015-12-01
影响因子：
3.8
通讯作者：
Gu, Yanhong
中科院分区：
文献类型：
--
作者：
Li, Qian;Zhang, Xiong;Gu, Yanhong
CPT-11作为化疗剂广泛用于癌症治疗。尽管它有良好的疗效，但在几十年的临床应用中出现了大量的副作用。迟发性腹泻在给药24 h后发生，发生率高达90%，为剂量限制性毒性。虽然许多投资已经对这一负面影响，真实的分子机制的延迟腹泻是知之甚少。在这项研究中，我们发现CPT-11促进巨噬细胞浸润到肠组织中，并激活NOD样受体家族，含pyrin结构域3（NLRP 3）炎性体，导致与DSS（葡聚糖硫酸钠）诱导的实验性结肠炎类似的强烈IL-1 β反应和结肠炎症。CPT-11加LPS致敏的小鼠骨髓源性巨噬细胞（BMDM）和人急性单核细胞白血病细胞（THP-1细胞）处于高度活化状态，通过ELISA和western blot检测显示caspase-1活性增加，并释放大量IL-1 β和IL-18。进一步的机制表明JNK和NF-κ B信号通路参与CPT-11激活的炎症反应。这些结果提示我们，NLRP 3-IL-1 β信号通路可能在CPT 11诱导的结肠炎中发挥重要作用。我们的研究结果为开发改善CPT-11临床意义的新策略提供了基础。(C)2015 Elsevier Inc. All rights reserved.
CPT-11 is widely used for cancer therapy as a chemotherapeutic agent. Despite its good efficacy, a large number of side effects appeared during decades of clinical application. Delayed diarrhea, at dose limiting toxicity, happens after 24 h of treatment and the rate of occurrence is up to 90%. Although many investments have been made on this negative impact, the real molecular mechanism of delayed diarrhea is poorly understood. In this study, we have discovered that CPT-11 promotes macrophage infiltration into intestinal tissues and activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, resulting in a robust IL-1 beta response and colonic inflammation similar to DSS (dextran sodium sulfate) induced experimental colitis. CPT-11 plus LPS primed mouse bone marrow-derived macrophages (BMDMs) and human acute monocytic leukemia cells (THP-1 cells) staying in a highly activated status, showing increased caspase-1 activity and releasing great amounts of IL-1 beta and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-kappa B signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1 beta signaling pathway might play an important role in CPT11-induced colitis. Our findings provide a basis for developing novel strategies that improve clinical implications of CPT-11. (C) 2015 Elsevier Inc. All rights reserved.