硫化氢通过AKT/GSK3β信号通路抑制系统性红斑狼疮患者淋巴细胞的异常增殖。
Hydrogen sulfide inhibits abnormal proliferation of lymphocytes via AKT/GSK3β signal pathway in systemic lupus erythematosus patients.
作者信息
Han Yanfang, Zeng Fanqin, Tan Guozhen, Yang Chuntao, Tang Hongfeng, Luo Yijin, Feng Jianqiang, Xiong Hui, Guo Qing
机构信息
Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; 107 Yanjian West Road, Guangzhou, China.
出版信息
Cell Physiol Biochem. 2013;31(6):795-804. doi: 10.1159/000350097. Epub 2013 May 31.
BACKGROUND/AIM: The abnormal activation of the AKT/GSK3β signal pathway in lymphocytes from systemic lupus erythematosus (SLE) patients plays an important role in the pathogenesis of the disease. Recently Hydrogen sulfide (H2S) has been recognized as a crucial gaseous signaling molecule, involved in regulation of cell proliferation. However, the role of H2S in regulating the abnormal activation of lymphocytes from SLE patients has not been established. This study was conducted to investigate the effect of H2S on lymphocytes and to explore the mechanisms involved.
METHODS
The lymphocytes were isolated from SLE patients with or without renal disease and healthy controls. The cells were treated as indicated in each experiment. Cell viability was analyzed by CCK-8. Cell cycle distribution was determined by flow cytometry. Western blot was used to detect the expression of phosphorylated AKT (ser473), GSK3β (ser9) and CDK2, p27(Kip1) and p21(WAF1/CIP1).
RESULTS
Our findings showed that proliferation of lymphocytes was stimulated following treatment with NaHS (a H2S donor) at low NaHS concentrations (<1mM) but inhibited at high NaHS concentrations (>2mM). Similar results were observed using GYY4137, which is a slow-releasing H2S donor. Pretreatment of lymphocytes from SLE patients with NaHS at high concentrations prior to exposure to phytohemagglutinin (PHA) significantly attenuated proliferation, evidenced by decrease in cell viability and S phase distribution of cell cycle. Pretreatment with NaHS decreased PHA-induced expression of CDK2, phosphorylation levels of AKT (ser473) and GSK3β (ser9) and increased the expression of p27(Kip1) and p21(WAF1/CIP1). Moreover, pretreatment with NaHS blunted the stimulation of SLE lymphocyte proliferation by GSK3β inhibitor lithium chloride.
CONCLUSION
These results demonstrate that H2S inhibits the abnormal activation of lymphocytes from SLE patients throuqh the AKT/GSK3β signal pathway.
背景/目的：系统性红斑狼疮（SLE）患者淋巴细胞中AKT/GSK3β信号通路的异常激活在该疾病的发病机制中起重要作用。近年来，硫化氢（H2S）已被公认为一种关键的气体信号分子，参与细胞增殖的调节。然而，H2S在调节SLE患者淋巴细胞异常激活中的作用尚未明确。本研究旨在探讨H2S对淋巴细胞的影响并探究其相关机制。
方法
从患有或未患有肾脏疾病的SLE患者及健康对照者中分离淋巴细胞。在每个实验中，细胞按指定方式处理。通过CCK-8分析细胞活力。采用流式细胞术测定细胞周期分布。运用蛋白质免疫印迹法检测磷酸化AKT（ser473）、GSK3β（ser9）以及CDK2、p27（Kip1）和p21（WAF1/CIP1）的表达。
结果
我们的研究结果表明，用低浓度（<1mM）的NaHS（一种H2S供体）处理后，淋巴细胞的增殖受到刺激，但在高浓度（>2mM）的NaHS处理时受到抑制。使用缓释H2S供体GYY4137也观察到了类似结果。在暴露于植物血凝素（PHA）之前，用高浓度的NaHS预处理SLE患者的淋巴细胞，显著减弱了增殖，这通过细胞活力降低和细胞周期S期分布得以证明。用NaHS预处理可降低PHA诱导的CDK2表达、AKT（ser473）和GSK3β（ser9）的磷酸化水平，并增加p27（Kip1）和p21（WAF1/CIP1）的表达。此外，用NaHS预处理可减弱GSK3β抑制剂氯化锂对SLE淋巴细胞增殖的刺激作用。
结论
这些结果表明，H2S通过AKT/GSK3β信号通路抑制SLE患者淋巴细胞的异常激活。
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