GSK3β与失代偿期肝硬化患者感染早期炎症因子过量表达密切相关

Glycogen synthase kinase 3 plays key role in the excessive expression of proinflammatory cytocine in the bacteria infectious in patients with decompensated cirrhosis

目的:探讨GSK3β在失代偿期肝硬化患者中感染早期炎症因子过表达中的作用及其机制。方法:分离失代偿期肝硬化患者与对照组的PBMCs,给予/不给予GSK3β抑制剂SB216763,同时使用LPS刺激,使用ELISA检测细胞上清液TNF-α、IL-6、IL-12的含量,使用Western blot检测细胞裂解液中p-GSK3β的表达情况。结果:LPS刺激肝硬化组PBMCs之后,可以产生过量的前炎症因子如TNF-α、IL-6、IL-12。GSK3β抑制剂SB216763抑制肝硬化组PBMCs的IL-12、TNF-α、IL-6的产生;LPS刺激肝硬化组患者PBMCs、GSK3β的磷酸化程度较对照组明显减低。结论:肝硬化患者PBMCs在LPS的刺激下,可以产生过量的前炎症因子如TNF-α、IL-6、IL-12,这是由于肝硬化患者中GSKβ的磷酸化减低,进而导致其活性增强而造成的;同时,肝硬化患者炎症细胞因子的过量产生,仍然可以被GSK3β的抑制剂所抑制。

Objective To investigated the role and mechanism of GSK3 in LPS-induced cytokine production in peripheral blood mononuclear cells （PBMCs） in patients with advanced cirrhosis. Methods Cells from the patients with cirrhosis and normal subjects were pre-incubated with or without GSK3 inhibitor （SB216763） for 1 h and then stimulated with LPS. The levels of TNF-α, IL-6 and IL-12 were assessed, by ELISA at 24 h, respectively. GSK3 phosphorylation was assessed using Western blot. Results Stimulated with LPS, PBMCs produced more TNF-α, IL-6 and IL-12. In cirrhotic PBMCs pretreated with GSK3 inhibitors, LPS-induced TNF- α, IL-6 and was weakened in IL-12p40 were significantly decreased. Phosphorylation of GSK3 LPS stimulated cirrhotic PBMCs. Conclusions In cirrhotic and normal PBMCs pretreated with GSK3 inhibitors, LPS-induced production of pro-inflammatory cytokines TNF-α and IL-12p40 may be significantly decreased. LPS-induced AKT- mediated phosphorylation of GSK3 on Ser9 found in normal monocytes could be abolished in cirrhotic cells.