The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock.
The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock.
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DOI：
10.1111/j.1582-4934.2007.00181.x
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发表时间：
2008-09
影响因子：
5.3
通讯作者：
Jo EK
中科院分区：
文献类型：
--
作者：
Yang CS;Ko SR;Cho BG;Shin DM;Yuk JM;Li S;Kim JM;Evans RM;Jung JS;Song DK;Jo EK
化合物K（C-K），一种原人参二醇的代谢物，先前显示具有免疫调节作用。在这里，我们描述了一种新的治疗作用，C-K在致命的脓毒症的治疗通过调节Toll样受体（TLR）4相关的信号通过糖皮质激素受体（GR）结合。在单核吞噬细胞中，C-K显著抑制TLR 4/脂多糖（LPS）诱导的NF-κB和丝裂原活化蛋白激酶（MAPK）的活化，以及促炎细胞因子的分泌。但C-K不影响TLR 3介导的IFN-β的表达和IRF-3的核转位。C-K与合成的糖皮质激素地塞米松竞争结合GR并以剂量依赖性方式激活含糖皮质激素反应元件（GRE）的报告质粒。此外，用GR拮抗剂RU 486或针对GR的siRNA阻断GR基本上逆转了C-K的抗炎作用。此外，TLR 4依赖性C-K抑制炎症反应基因是通过破坏p65/干扰素调节因子复合物介导的。重要的是，用C-K预处理或后处理通过降低它们的全身炎性细胞因子水平和通过逆转败血症的致死性后遗症，显著地将小鼠从革兰氏阴性细菌LPS诱导的致死性休克中拯救出来。总的来说，这些结果表明，C-K，作为GR的功能性配体，调节不同的TLR 4介导的炎症反应，并提出了一种新的治疗革兰氏阴性脓毒性休克。
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.
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影响因子：
6.4
作者：
Akira, S;Hoshino, K
通讯作者：
Hoshino, K
影响因子：
4.1
作者：
Lee, YJ;Chung, E;Lee, SK
通讯作者：
Lee, SK
影响因子：
6.4
作者：
Jung, SH;Woo, MS;Kim, HS
通讯作者：
Kim, HS
影响因子：
8.4
作者：
Lee, YN;Lee, HY;Kim, KW
通讯作者：
Kim, KW
影响因子：
5.3
作者：
Boehmer, ED;Meehan, MJ;Kovacs, EJ
通讯作者：
Kovacs, EJ