Libertellenone M, a diterpene derived from an endophytic fungus Phomopsis sp. S12, protects against DSS-induced colitis via inhibiting both nuclear translocation of NF-κB and NLRP3 inflammasome activation

• Published in: International immunopharmacology 2020-03, Vol.80, p.106144, Article 106144
• Main Authors: Fan, Minmin, Xiang, Gang, Chen, Jingwei, Gao, Jian, Xue, Wenwen, Wang, Yixuan, Li, Wuhao, Zhou, Lin, Jiao, Ruihua, Shen, Yan, Xu, Qiang
• Format: Article
• Language: English
• Subjects: Activation; Animals; Anti-inflammatory; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Ascomycota; Caspase-1; Colitis; Colitis - chemically induced; Colitis - drug therapy; Colitis - immunology; Colitis - pathology; Colon; Colon - drug effects; Colon - immunology; Colon - pathology; Cytokines; Cytokines - genetics; Cytokines - immunology; Dextran; Dextran Sulfate; Dextrans; Diterpenes; Diterpenes - pharmacology; Diterpenes - therapeutic use; Drug development; Endophytes; Endophytic fungus; Experimental colitis; Female; Fungi; IL-1β; Immunosuppressive agents; Inflammasomes; Inflammasomes - antagonists & inhibitors; Inflammasomes - immunology; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 18; Intestine; Libertellenone M; Lipopolysaccharides; Macrophages; Metabolites; Mice; Mice, Inbred C57BL; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; NLRP3 inflammasome; Nuclear transport; Phomopsis; RAW 264.7 Cells; Transcription Factor RelA - antagonists & inhibitors; Transcription Factor RelA - immunology; Translocation
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2019.106144

[Display omitted] •Libertellenone M is derived from an endophytic fungus.•Libertellenone M selectively inhibited IL-1β and IL-18 expression by macrophages.•Libertellenone M inhibited the nuclear translocation of NF-κB in macrophages.•Libertellenone M inactivated NLRP3 inflammasome by interrupting its assembly.•Libertellenone M attenuated DSS-induced acute colitis in mice. NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for inflammatory bowel diseases. In this study, we found that Libertellenone M (Lib M), a secondary metabolite from the endophytic fungus Phomopsis sp. S12, has anti-inflammatory potential both in vitro and in vivo. Lib M selectively inhibited the expression of proinflammatory cytokine IL-1β and IL-18 in LPS-activated macrophages. The cleavage of pro-caspase 1 was remarkably reduced by Lib M in macrophages stimulated with three NLRP3 inflammasome activators. Administering Lib M attenuated dextran sulfate sodium-induced experimental acute colitis in mice and significantly reduced the production of these cytokines and cleaved caspase 1 in colon tissues. Apart from inhibition of NLRP3 inflammasome assembly, Lib M also suppressed NF-κB nuclear translocation in macrophages. Taken together, these findings suggest that Lib M-mediated inhibition of NLRP3 inflammasome activation could protect against colitis-like inflammatory diseases, and that this compound derived from a plant-associated fungus might inspire the exploration of novel immunosuppressive agents.