β-caryophyllene protects against D-galactosamine and lipopolysaccharide-induced hepatic failure

β-caryophyllene (4,11,11-trimethyl-8-methylene-bicyclo[7.2.0]undec-4-ene) is a natural bicyclic sesquiterpene isolated from Agastache rugosa (Fisch. et Meyer) O. Kuntze (Labiatae) has been shown to exhibit antioxidant and anti-inflammatory properties. Fulminant hepatic failure (FHF) is a dramatic clinical syndrome characterized by massive inflammation and hepatocellular death. Inflammasome plays an important role in the regulation of cellular redox balance, apoptosis, and inflammation in the FHF. In this study, we examined the hepatoprotective mechanisms of β-caryophyllene against D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced hepatic failure. Mice were given an intraperitoneal injection of β-caryophyllene (50, 100 and 200 mg/kg) or vehicle alone (10% Tween 80 saline) 1h before GalN (800 mg/kg)/LPS (40 µg/kg), and sacrificed at 1 and 6h after GalN/LPS injection. GalN/LPS markedly increased mortality and serum aminotransferase activity, which were attenuated by β-caryophyllene. GalN/LPS increased serum tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 levels, and these increases were attenuated by β-caryophyllene. GalN/LPS significantly increased protein expression of toll-like receptor (TLR) 4, myeloid differentiation primary response gene 88 and TNF receptor-associated factor 6, nuclear protein expression of nuclear factor kB, and these increases were attenuated by β-caryophyllene. GalN/LPS activated NLRP3 (NACHT, LRR, and pyrin domain-containing protein 3) inflammasome as indicated by increased mature IL-1β, caspase-1, apoptosis-associated speck-like protein containing a CARD, and NLRP3 protein expressions. This activation was attenuated by β-caryophyllene. Our finding suggests that β-caryophyllene protects against GalN/LPS-induced liver injury through suppression of TLR4 signaling and inflammasome pathway.

Keywords: β-caryophyllene, Agastache rugosa, fulminant hepatic failure, hepatoprotection, toll-like receptor, inflammasome