Genipin protects D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the necroptosis-mediated inflammasome signaling
Genipin protects D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the necroptosis-mediated inflammasome signaling
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DOI：
10.1016/j.ejphar.2017.07.024
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发表时间：
2017-10-05
影响因子：
5
通讯作者：
Lee, Sun-Mee
中科院分区：
文献类型：
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作者：
Seo, Min-Jong;Hong, Jeong-Min;Lee, Sun-Mee
急性肝衰竭（ALF）是一种由大量炎症和肝细胞死亡引起的危及生命的综合征。坏死坏死是一种由受体相互作用蛋白激酶（RIP） 1和RIP3控制的程序性细胞死亡，已被证明在通过其他细胞内信号传导之间的串扰调节炎症中发挥重要作用。炎性小体是一种主要的细胞内多蛋白，通过介导免疫细胞浸润诱导炎症反应，从而增强损伤。栀子提取物Genipin具有抗炎、抗氧化和抗细胞凋亡的作用。本研究探讨了格尼平对d -半乳糖胺（GalN）和脂多糖（LPS）诱导的ALF的肝保护机制，特别是坏死性坏死和炎性小体之间的相互作用。小鼠在注射GalN (800 mg/kg)/LPS （40 mu g/kg）前1小时腹腔注射genipin（25、50和100 mg/kg）或necrostatin-1 (nec1，一种坏死抑制剂，1.8 mg/kg)，并在注射GalN/LPS后3小时杀死小鼠。Genipin提高了GalN/LPS注射后小鼠的存活率，降低了血清转氨酶活性和炎症因子的升高。Genipin降低了GalN/ lps诱导的RIP3，磷酸化RIP1和RIP3蛋白表达，以及RIP1/RIP3坏死体复合物的增加，类似于Nec-1的作用。GalN/LPS显著提高了高迁移率组1和白细胞介素-33的水平，而genipin和Nec-1则降低了高迁移率组1和IL -33的水平。此外，与Nec-1类似，genipin降低了GalN/ lps，导致NLRP3、ASC和caspase-1蛋白表达水平升高，炎症小体成分以及肝脏和血清IL-1 β水平升高。综上所述，我们的研究结果表明，genipin通过抑制坏死介导的炎症小体信号传导，改善了GalN/ lps诱导的肝细胞损伤。
Acute liver failure (ALF) is a life-threatening syndrome resulting from massive inflammation and hepatocyte death. Necroptosis, a programmed cell death controlled by receptor-interacting protein kinase (RIP) 1 and RIP3, has been shown to play an important role in regulating inflammation via crosstalk between other intracellular signaling. The inflammasome is a major intracellular multiprotein that induces inflammatory responses by mediating immune cell infiltration, thus potentiating injury. Genipin, a major active compound of the gardenia fruit, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. This study investigated the hepatoprotective mechanisms of genipin on D-galactosamine (GalN) and lipopolysaccharide (LPS)induced ALF, particularly focusing on interaction between necroptosis and inflammasome. Mice were given an intraperitoneal injection of genipin (25, 50, and 100 mg/kg) or necrostatin-1 (Nec-1, a necroptosis inhibitor; 1.8 mg/kg) 1 h prior to GalN (800 mg/kg)/LPS (40 mu g/kg) injection and were killed 3 h after GalN/LPS injection. Genipin improved the survival rate and attenuated increases in serum aminotransferase activities and inflammatory cytokines after GalN/LPS injection. Genipin reduced GalN/LPS-induced increases in RIP3, phosphorylated RIP1 and RIP3 protein expression, and RIP1/RIP3 necrosome complex, similar to the effects of Nec-1. GalN/LPS significantly increased serum levels of high-mobility group box 1 and interleukin (IL)-33, which were attenuated by genipin and Nec-1. Moreover, similar to Nec-1, genipin attenuated GalN/LPSinduced increases in the protein expression levels of NLRP3, ASC, and caspase-1, inflammasome components, and levels of liver and serum IL-1 beta. Taken together, our findings suggest that genipin ameliorates GalN/LPSinduced hepatocellular damage by suppressing necroptosis-mediated inflammasome signaling.