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

Abstract

Ethnopharmacological relevance: 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.

Aim of the study: 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.

Materials and methods: 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.

Results: 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.

Conclusions: 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.

Keywords: IL-1β; Inflammasome; Macrophage; Panaxadiol; ZFP91.