Suppression of liver injury through inhibition of MyD88 signaling in a mouse model of fulminant hepatitis by 18β-glycyrrhetinic acid (142.11)

Abstract

Abstract Fulminant hepatitis, develops secondary to infection, toxin or immune mediated attack, is a rare but potentially fatal disease. However, the molecular mechanisms underlying are not well known. 18β-glycyrrhetinic acid (GA), the major bioactive component of licorice root extract, has a protective effect on hepatic injury and exhibits anti-inflammatory activity. Here we investigate the potential role of GA in a mouse model of fulminant hepatitis induced by injection of Propionibacterium acnes (P. acnes) and LPS. GA or vehicle control was administered intraperitoneally daily 1 d after P. acnes priming. The results revealed that GA treatment significantly improved mouse mortality and ameliorated liver injury through inhibition of the activation and proliferation of liver-infiltrating CD4+ T cells and the production of serum pro-inflammatory cytokines such as IFN-γ and TNF-α. However, GA exhibited no direct effect on the proliferation of liver-infiltrating CD4+ T cells, but by reduced recruitment of CD11c+B220- DC precursors into the liver, which is mediated by the inhibition of MIP-1α expression in Kupffer cells by GA. More importantly, GA inhibited the activation of Kupffer cells by down-regulating MyD88 expression and its down-stream signal NF-κB activation. Taken together, our results suggest that GA exhibits anti-inflammatory effects through inhibition of MyD88 signaling in a mouse model of fulminant hepatitis.