期刊
MOLECULAR IMMUNOLOGY
卷 104, 期 -, 页码 11-19出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2018.09.004
关键词
Curcumin; NLRP3 inflammasome; IL-1 beta; Inflammatory bowel diseases; Dextran sulfate sodium
资金
- Xinhua Hospital [15YJ11]
- Natural Science Foundation of Shanghai [16ZR1428500]
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition [11DZ2260500]
Background NLRP3 inflammasome mediates IL-1 beta maturation, therefore plays a vital role in the development of IBD. Curcumin is known for possessing strong anti-inflammatory property. Objective: The present study was to investigate the protective effects of curcumin on dextran sulfate sodium (DSS)-induced colitis through inhibiting NLRP3 inflammasome activation and IL-1 beta production. Methods: LPS-primed macrophages were treated with curcumin prior to DSS triggering NLRP3 inflammasome activation, IL-1j3 secretion and ASC oligomerization were observed. The mechanisms of curcumin in the inhibition of DSS-induced inflammasome activation were explored. Curcumin or caspase-1/NLRP3 inhibitor was administrated respectively in DSS-induced colitis mouse model. The changes of body weight, disease activity index, colon length were measured. Additionally, mature IL-1 beta and other inflammatory cytokines, MPO activity and histopathological damage were analyzed for the evaluation of colitis severity. Results: NLRP3 inflammasome activation was dramatically inhibited by curcumin in DSS-stimulated macrophages, as evidenced by decreased IL-1 beta secretion, less caspase-1 activation and ASC specks. Mechanistically, curcumin prevented DSS-induced K+ efflux, intracellular ROS formation and cathepsin B release, three major cellular events mediating NLRP3 inflammasome activation. In DSS-induced colitis, curcumin administration significantly ameliorated colitis symptoms by reducing weight loss, DAI and colon length shortening. Meanwhile, curcumin significantly decreased the expression of multiple inflammatory cytokines (including mature IL-1 beta, IL-6, MCP-1), MPO activity, caspase-1 activity as well as histopathological damage. Furthermore, blockage of NLRP3 inflammasome activation in vivo with specific NLRP3 inhibitor abrogated the further inhibitory effect of curcumin on DSS-induced colitis. Conclusion: Curcumin could strongly suppress DSS-induced NLRP3 inflammsome activation and alleviate DSSinduced colitis in mice, thus it may be a promising candidate drug in clinical application for IBD therapy.
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