title: Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant hepatic failure in d-galactosamine-sensitized mice by up-regulating expression of interleukin-1 receptor-associated kinase-M.
abstract: Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti-inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100mg/kg) 1h before lipopolysaccharide (LPS)/d-galactosamine (D-GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed. Toll like receptor 4 (TLR4), interleukin-1 receptor-associated kinases (IRAKs), activation of mitogen-activated protein kinases (MAPKs) and NF-κB, and production of TNF-α were assessed by flow cytometry, western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Our results showed that pretreatment with GA protected mice against LPS/D-GalN-induced fulminant hepatic failure (FHF), including a dose-dependent alleviation of mortality and ALT/AST elevation, ameliorating hepatic pathological damage, and decreasing TNF-α release. Moreover, GA inhibited LPS-induced activation of MAPKs and NF-κB in response to LPS, but the expression of TLR4 was not affected in vivo and in vitro. Notably, GA pretreatment in vivo suppressed IRAK-1 activity while inducing IRAK-M expression. Silencing of IRAK-M expression with siRNA blocked these beneficial effects of GA on the activation of MAPKs and NF-κB as well as TNF-α production in LPS-primed macrophages. Taken together, we conclude that GA could prevent LPS/D-GalN-induced FHF. The underlying mechanisms may be related to up-regulation of IRAK-M, which in turn caused deactivation of IRAK-1 and subsequent MAPKs and NF-κB, resulting in inhibiting TNF-α production.
authors.affiliation: Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Anatomy, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Gong
authors.affiliation: Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Kuang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China. Electronic address: jywan@cqmu.edu.cn.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Wan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005688:Galactosamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D005688:Galactosamine; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D006034:Glycyrrhetinic Acid
keywords: Fulminant hepatic failure; Glycyrrhetinic acid; IRAK-M; LPS; TLR4