CPT-11 activates NLRP3 inflammasome through JNK and NF-κB signalings

Journal Article · Tue Dec 01 04:00:00 EST 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.09.025· OSTI ID:22687819

Li, Qian ^[1]; Zhang, Xiong ^[2]; Wang, Weicheng; Li, LeLe ^[1]; Xu, Qiang ^[2]; Wu, Xudong ^[2]; Gu, Yanhong ^[1]

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1. Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, 300, Guangzhou Road, Nanjing 210029 (China)
2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210046 (China)

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-1β 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-1β and IL-18 as detected by ELISA and western blot. A further mechanism showed that JNK and NF-κB signaling pathways participated in inflammatory responses activated by CPT-11. These results prompted us to suggest that the NLRP3-IL-1β 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. - Highlights: • CPT-11 induced experimental colitis in vivo. • CPT-11 induced intestine injury and macrophage infiltration. • CPT-11 significantly elevated levels of macrophage derived inflammatory cytokines in mice intestines. • CPT-11 activated NLRP3 inflammasome in vitro and in vivo. • CPT-11 activated JNK and NF-κB signalings in THP-1 and BMDMs.

• OSTI ID: 22687819
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 289; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BONE MARROW
DEXTRAN
DIARRHEA
ENZYME IMMUNOASSAY
IN VITRO
IN VIVO
INFLAMMATION
INJURIES
INTESTINES
LEUKEMIA
LYMPHOKINES
MACROPHAGES
MICE
RECEPTORS
SIDE EFFECTS
SKELETON
SODIUM
SODIUM SULFATES
THERAPY
TOXICITY