PMID- 26431797 OWN - NLM STAT- MEDLINE DCOM- 20160308 LR - 20190816 IS - 1096-0333 (Electronic) IS - 0041-008X (Linking) VI - 289 IP - 2 DP - 2015 Dec 1 TI - CPT-11 activates NLRP3 inflammasome through JNK and NF-kappaB signalings. PG - 133-41 LID - S0041-008X(15)30098-3 [pii] LID - 10.1016/j.taap.2015.09.025 [doi] AB - 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 24h 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-1beta 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-1beta and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-kappaB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1beta 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. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Li, Qian AU - Li Q AD - Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China. FAU - Zhang, Xiong AU - Zhang X AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, China. FAU - Wang, Weicheng AU - Wang W AD - Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China. FAU - Li, LeLe AU - Li L AD - Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China. FAU - Xu, Qiang AU - Xu Q AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, China. Electronic address: molpharm@163.com. FAU - Wu, Xudong AU - Wu X AD - State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046, China. Electronic address: xudongwu@nju.edu.cn. FAU - Gu, Yanhong AU - Gu Y AD - Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029, China. Electronic address: guluer@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150930 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (Anti-Inflammatory Agents) RN - 0 (CXCL8 protein, human) RN - 0 (Carrier Proteins) RN - 0 (IL1B protein, human) RN - 0 (IL1B protein, mouse) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-8) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Topoisomerase I Inhibitors) RN - 7673326042 (Irinotecan) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 3.4.22.36 (Caspase 1) RN - XT3Z54Z28A (Camptothecin) SB - IM MH - Animals MH - Anti-Inflammatory Agents/pharmacology MH - Camptothecin/*analogs & derivatives/toxicity MH - Carrier Proteins/*metabolism MH - Caspase 1/metabolism MH - Cell Line, Tumor MH - Colitis/*chemically induced/drug therapy/enzymology/genetics/immunology/pathology MH - Colon/*drug effects/enzymology/immunology MH - Diarrhea/chemically induced/enzymology/immunology/pathology MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Inflammation Mediators/*metabolism MH - Interleukin-1beta/metabolism MH - Interleukin-8/metabolism MH - Irinotecan MH - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism MH - Lipopolysaccharides/pharmacology MH - Macrophages/*drug effects/enzymology/immunology MH - Mice, Inbred C57BL MH - NF-kappa B/antagonists & inhibitors/*metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein MH - Permeability MH - Protein Kinase Inhibitors/pharmacology MH - Signal Transduction/*drug effects MH - Time Factors MH - Topoisomerase I Inhibitors/*toxicity OTO - NOTNLM OT - CPT-11 OT - Delayed diarrhea OT - Experimental colitis OT - JNK OT - NF-kappaB OT - NLRP3 inflammasome EDAT- 2015/10/04 06:00 MHDA- 2016/03/10 06:00 CRDT- 2015/10/04 06:00 PHST- 2015/05/03 00:00 [received] PHST- 2015/09/23 00:00 [revised] PHST- 2015/09/28 00:00 [accepted] PHST- 2015/10/04 06:00 [entrez] PHST- 2015/10/04 06:00 [pubmed] PHST- 2016/03/10 06:00 [medline] AID - S0041-008X(15)30098-3 [pii] AID - 10.1016/j.taap.2015.09.025 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2015 Dec 1;289(2):133-41. doi: 10.1016/j.taap.2015.09.025. Epub 2015 Sep 30.