The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock.

Abstract

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-kappaB 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-beta 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.

• Authors: Chul-Su Yang, Sung-Ryong Ko, Byung-Goo Cho, Dong-Min Shin, Jae-Min Yuk, Shengjin Li, Jin-Man Kim, Ronald M Evans, Jun-Sub Jung, Dong-Keun Song, Eun-Kyeong Jo
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) 2008 Sep-Oct Vol. 12 Issue 5A Pg. 1739-53 ISSN: 1582-1838 [Print] England
• PMID: 18053081 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Endotoxins
• Ginsenosides
• Ligands
• Lipopolysaccharides
• Receptors, Glucocorticoid
• Toll-Like Receptors
• ginsenoside M1

Topics

• Animals
• Cells, Cultured
• Cytokines (metabolism)
• Drug Tolerance
• Endotoxins (toxicity)
• Ginsenosides (chemistry, metabolism, pharmacology)
• Humans
• Ligands
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• Receptors, Glucocorticoid (agonists, metabolism)
• Shock, Septic (chemically induced, prevention & control)
• Signal Transduction (drug effects)
• Substrate Specificity
• Survival Rate
• Toll-Like Receptors (metabolism)