Open AccessThe ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin‐induced lethal shock
Author(s) -
Yang ChulSu,
Ko SungRyong,
Cho ByungGoo,
Shin DongMin,
Yuk JaeMin,
Li Shengjin,
Kim JinMan,
Evans Ronald M.,
Jung JunSub,
Song DongKeun,
Jo EunKyeong
Publication year - 2008
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2007.00181.x
Subject(s) - glucocorticoid receptor , glucocorticoid , tlr4 , pharmacology , lipopolysaccharide , agonist , receptor , biology , chemistry , inflammation , endocrinology , immunology , biochemistry
Compound K (C‐K), a protopanaxadiol ginsenoside metabolite, was previously shown to have immunomodulatory effects. Here, we describe a novel therapeutic role for C‐K in the treatment of lethal sepsis through the modulation of Toll‐like receptor (TLR) 4‐associated signalling via glucocorticoid receptor (GR) binding. In mononuclear phagocytes, C‐K significantly repressed the activation of TLR4/lipopolysaccharide (LPS)‐induced NF‐κB and mitogen‐activated protein kinases (MAPKs), as well as the secretion of pro‐inflammatory cytokines. However C‐K did not affect the TLR3‐mediated expression of interferon‐β or the nuclear translocation of IRF‐3. C‐K competed with the synthetic glucocorticoid dexamethasone for binding to GR and activated glucocorticoid responsive element (GRE)‐containing reporter plasmids in a dose‐dependent manner. In addition, the blockade of GR with either the GR antagonist RU486 or a siRNA against GR substantially reversed the anti‐inflammatory effects of C‐K. Furthermore, TLR4‐dependent repression of inflammatory response genes by C‐K was mediated through the disruption of p65/interferon regulatory factor complexes. Importantly, pre‐ or post‐treatment with C‐K significantly rescued mice from Gram‐negative bacterial LPS‐induced lethal shock by lowering their systemic inflammatory cytokine levels and by reversing the lethal sequelae of sepsis. Collectively, these results demonstrate that C‐K, as a functional ligand of GR, regulates distinct TLR4‐mediated inflammatory responses, and suggest a novel therapy for Gram‐negative septic shock.