The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock.
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.
Yang
Chul-Su
CS
Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, S. Korea.
Ko
Sung-Ryong
SR
Cho
Byung-Goo
BG
Shin
Dong-Min
DM
Yuk
Jae-Min
JM
Li
Shengjin
S
Kim
Jin-Man
JM
Evans
Ronald M
RM
Jung
Jun-Sub
JS
Song
Dong-Keun
DK
Jo
Eun-Kyeong
EK
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004361:Drug Tolerance; D004731:Endotoxins / Q000633:toxicity*; D036145:Ginsenosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D015996:Survival Rate; D051193:Toll-Like Receptors / Q000378:metabolism
D016207:Cytokines; D004731:Endotoxins; D036145:Ginsenosides; D008024:Ligands; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D051193:Toll-Like Receptors; C112772:ginsenoside compound K