Panaxadiol inhibits IL-1β secretion by suppressing zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages

The use of Panax ginseng C.A.Mey. in traditional Chinese medicine dates back to about 5000 years ago thanks to its several beneficial and healing properties. Panaxadiol is a triterpenoid sapogenin monomer found in the roots of Panax ginseng C.A.Mey. and has been proven to have various bio-activities such as anti-inflammatory, anti-tumour and neuroprotective effects.The present study focuses on investigating the inflammation inhibitory effect and mechanism of panaxadiol by regulating zinc finger protein 91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs in macrophages.In vitro, the underlying mechanisms by which panaxadiol inhibits ZFP91-regulated IL-1β expression were investigated using molecular docking, western blotting, RT-PCR, ELISA, immunofluorescence, and immunoprecipitation assays. In vivo, colitis was induced by oral administration of DSS in drinking water, and peritonitis was induced by an intraperitoneal injection of alum. Recombinant adeno-associated virus (AAV serotype 9) vector was used to establish ZFP91 knockdown mouse.We confirmed that panaxadiol inhibited IL-1β secretion by suppressing ZFP91 in macrophages. Further analysis revealed that panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome. Meanwhile, panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of MAPKs. In vivo, prominent anti-inflammatory effects of panaxadiol were demonstrated in a DSS induced acute colitis mouse model and in an alum-induced peritonitis model by suppressing ZFP91-regulated secretion of inflammatory mediators, consistent with the results of the AAV-ZFP91 knockdown in mice.We report for the first time that panaxadiol inhibited IL-1β secretion by suppressing ZFP91-regulated activation of non-canonical caspase-8 inflammasome and MAPKs, providing evidence for anti-inflammation mechanism of panaxadiol treatment for inflammatory diseases.