ReferenceID 1572
Convallatoxin inhibits IL-1β production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1β ubiquitination and caspase-8 inflammasome activity
Br J Pharmacol
BACKGROUND AND PURPOSE: ZFP91 positively regulates IL-1beta production in macrophages and may be a potential therapeutic target to treat inflammatory-related diseases. Therefore, we investigated whether this process is m
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- Reference Id
- 1572
- Evidence Id
- 18162
- Core Evidence Id
- 18162
- Source Reference Id
- 3147
- Herb2 Reference Id
- HBREF003944
- Subject Paper Key
- HBIN021403_34825365
- Pubmed Id
- 34825365
- Doi
- 10.1111/bph.15758
- Paper Title
- Convallatoxin inhibits IL-1β production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1β ubiquitination and caspase-8 inflammasome activity
- Paper Abstract
- BACKGROUND AND PURPOSE: ZFP91 positively regulates IL-1beta production in macrophages and may be a potential therapeutic target to treat inflammatory-related diseases. Therefore, we investigated whether this process is modulated by convallatoxin, which is a cardiac glycoside isolated from the traditional Chinese medicinal plant Adonis amurensis Regel et Radde. EXPERIMENTAL APPROACH: In vitro, the underlying mechanisms by which convallatoxin inhibits ZFP91-regulated IL-1beta expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence, and immunoprecipitation assays. In vivo, liver injury was induced by an intraperitoneal injection of D-GalN and LPS, colitis was induced by oral administration of DSS in drinking water, and peritonitis was induced by an intraperitoneal injection of alum. KEY RESULTS: We confirmed that convallatoxin inhibited the release of IL-1beta by downregulating ZFP91. Importantly, we found that convallatoxin significantly reduced K63-linked polyubiquitination of pro-IL-1beta regulated by ZFP91 and decreased the efficacy of pro-IL-1beta cleavage. Moreover, convallatoxin suppressed ZFP91-mediated activation of the non-canonical caspase-8 inflammasome and MAPK signaling pathways in macrophages. Furthermore, we showed that ZFP91 promoted the assembly of the caspase-8 inflammasome complex, whereas convallatoxin treatment reversed this result. In vivo studies further demonstrated that convallatoxin ameliorated D-GalN/LPS-induced liver injury, DSS-induced colitis, and alum-induced peritonitis by downregulating ZFP91. CONCLUSION AND IMPLICATIONS: We report for the first time that convallatoxin-mediated inhibition of ZFP91 is an important regulatory event that prevents inappropriate inflammatory responses to maintain of immune homeostasis. This mechanism provides new perspectives for the development of convallatoxin as a novel anti-inflammatory drug targeting ZFP91.
- Journal
- Br J Pharmacol
- Publish Year
- 2021
- Experiment Subject
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Colitis; Alum-induced Peritonitis; Inflammatory-related Diseases; Peritonitis
- Paper Title Cn
- Paper Title En
- Convallatoxin inhibits IL-1β production by suppressing zinc finger protein 91 (ZFP91)-mediated pro-IL-1β ubiquitination and caspase-8 inflammasome activity
- Bilingual Status
- semi_complete