Genipin Attenuates Sepsis by Inhibiting Toll-Like Receptor Signaling
Genipin Attenuates Sepsis by Inhibiting Toll-Like Receptor Signaling
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DOI：
10.2119/molmed.2011.00308
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发表时间：
2012-03-01
影响因子：
5.7
通讯作者：
Lee, Sun-Mee
中科院分区：
文献类型：
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作者：
Kim, Tae-Hoon;Yoon, Seong-Jin;Lee, Sun-Mee
脓毒症的发病机制以导致组织损伤和器官衰竭的压倒性炎症反应为特征。Toll样受体（TLR）信号传导对于脓毒症期间诱导高炎症反应和组织损伤至关重要。京尼平是京尼平苷的苷元，具有抑菌和抗菌活性。本研究的目的是检验京尼平通过抑制TLR信号传导降低脓毒症期间多器官功能障碍和死亡率的假设。雄性ICR通过盲肠结扎和穿孔（CLP）或内毒素血症（LPS）进行脓毒症。CLP后立即静脉内或LPS处理后腹膜内给予不同剂量的京尼平（1、2.5和5 mg/kg）或溶媒。在另一组存活测试中，在CLP后0和24小时用2.5mg/kg京尼平处理小鼠，发现京尼平改善存活并减弱多器官功能障碍。京尼平减弱促炎细胞因子的产生和高迁移率族蛋白1（HMGB 1）的释放。京尼平阻止了TLR 2和TLR 4、髓样分化因子88和Toll/白细胞介素-1受体结构域的衔接蛋白，诱导干扰素-β过表达。京尼平可阻止丝裂原活化蛋白激酶和干扰素调节因子3的磷酸化以及核因子（NF）-κ B的易位。此外，京尼平还能减弱脂多糖诱导的内毒素血症中血清肿瘤坏死因子-α和HMGB 1的升高。在RAW264.7细胞中，京尼平抑制了Pam 3CSK 4和LPS介导的亚硝酸盐和促炎细胞因子的产生。京尼平通过干扰TLR信号转导减轻脓毒症期间的死亡率和器官损伤。因此，京尼平可能是一种潜在的治疗药物，用于治疗脓毒症。在线地址：http://www.molmed.org doi：10.2119/molmed.2011.00308
The pathogenesis of sepsis is characterized by overwhelming inflammatory responses that lead to tissue damage and organ failure. Toll-like receptor (TLR) signaling is crucial for induction of hyperinflammatory responses and tissue injury during sepsis. Genipin, an aglycon of geniposide, has antiinflammatory and antimicrobial activities. The purpose of this study was to test the hypothesis that genipin reduces multiple organ dysfunction and mortality during sepsis through inhibition of TLR signaling. Male ICR were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia by lipopolysaccharide (LPS). Various doses of genipin (1, 2.5 and 5 mg/kg) or a vehicle were administered intravenously immediately after CLP or intraperitoneally after LPS treatment. In another set of survival tests, mice were treated with 2.5 mg/kg of genipin 0 and 24 h after CLP Genipin was found to improve survival and to attenuate multiple organ dysfunction. Genipin attenuated production of proinflammatory cytokines and release of high-mobility group box 1 (HMGB1). Genipin prevented TLR2 and TLR4, myeloid differentiation factor 88 and the Toll/interleukin-1 receptor domain-containing adaptor protein, inducing interferon-beta overexpression. Phosphorylation of mitogen-activated protein kinases and interferon regulatory factor 3 and translocation of nuclear factor (NF)-kappa B were prevented by genipin. Moreover, genipin attenuated increases in serum tumor necrosis factor-alpha and HMGB1 in LPS-induced endotoxemia. Pam3CSK4- and LPS-mediated production of nitrites and proinflammatory cytokines was suppressed by genipin in RAW264.7 cells. Genipin attenuated mortality and organ injuries during sepsis through interference with TLR signaling. Therefore, genipin might be useful as a potential therapeutic agent for treatment of sepsis. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00308