糖原合成酶激酶-3β在神经保护中的研究进展

背景 糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)是一种多功能丝氨酸/苏氨酸蛋白激酶,在中枢神经系统中表达丰富.近期研究表明GSK-3β活性异常参与多种疾病的病理生理机制.目的 分析总结GSK-3β活性调节在神经保护中作用及机制的文献资料.内容 描述GSK-3β的基本结构、组成;调节方式;GSK-3β抑制剂在脑缺血/再灌注损伤中的保护作用及相关机制. 趋向 GSK-3β抑制剂对脑缺血/再灌注损伤具有保护作用,其特异亚型抑制剂及基因沉默的研发在脑缺血/再灌注损伤治疗方面具有良好的应用前景.     

糖原合成酶激酶3与前列腺癌研究进展

糖原合成酶激酶3(GSK-3α和GSK-3β)是一种高度保守的丝氨酸/苏氨酸蛋白激酶,它能作用于多种底物,参与细胞增殖与存活、糖原代谢和自噬等调控。免疫组化研究发现GSK-3的两个亚型中,GSK-3α主要在雄激素依赖性前列腺癌表达增强,而GSK-3β则在雄激素非依赖前列腺癌中表达升高,且GSK-3β参与雄激素受体的转录活性调控和体内前列腺癌的生长。动物实验研究证实氯化锂等GSK-3特异性抑制剂对前列腺癌异植瘤生长具有显著抑制作用。GSK-3抑制剂有可能作为晚期前列腺癌的辅助治疗药物。     

糖原合酶激酶3β抑制剂对前列腺癌细胞裸鼠移植瘤生长的抑制作用

目的 研究糖原合酶激酶3β(glycogen synthase kinase-3β,GSK-3β)抑制剂抗前列腺癌细胞裸鼠移植瘤生长的效用. 方法 建立前列腺癌PC-3和LNCaP/Bcl-xL细胞株裸鼠移植瘤模型,观测GSK-3β抑制剂氯化锂(LiCl)及SB216763腹腔内给药后移植瘤重量及体积的变化.同时通过BrdU掺入的免疫组化染色探讨移植瘤的增殖状态,TUNEL染色比较对移植瘤细胞凋亡的影响. 结果 LiCl及SB216763均可明显抑制移植瘤生长(P＜0.05).与对照组相比,LiCl给药组细胞BrdU标记明显降低(P＜0.05),TUNEL染色差异无统计学意义. 结论 抑制GSK-3β活性可抑制前列腺癌裸鼠移植瘤细胞在体内的生长,其中LiCl可能通过干扰癌细胞DNA复制发挥作用.     

γ-氨基丁酸B型受体对结肠癌HCT116细胞周期的影响

目的利用人结肠癌细胞株HCT116细胞为研究模型,探究γ-氨基丁酸B型受体（GABABR）/糖原合成激酶3β（GSK-3β）/核转录因子（NF-κB）信号通路对结肠肿瘤细胞HCT116周期的影响,明确GABABR调控结肠癌细胞增殖的机制。 方法使用人结肠癌细胞株HCT116细胞为模型,构建针对GABABR的shRNA,流式细胞仪检测不同刺激条件下HCT116细胞周期分布,四甲基偶氮唑盐微量酶反应比色法（MTT）、5-溴脱氧尿嘧啶核苷（Brdu）法检测细胞的增殖能力变化。 结果GABABR可调控HCT116细胞的增殖。GABABR激动剂巴氯芬将HCT116细胞滞留在G1期,GSK-3β激动剂wort能逆转巴氯芬对结肠癌的该作用;GSK-3β抑制剂SB216763处理后,HCT116细胞增殖得到抑制,而NF-κB激动剂PMA可以阻断此作用;NF-κB激动剂PDTC能够回救敲低GABABR所引起的HCT116细胞增殖抑制,Akt抑制剂MK-2206 2HCl能逆转巴氯芬、SB216763对HCT116细胞增殖的抑制作用。 结论GABABR/GSK-3β/NF-κB信号通路可以调控结肠癌细胞增殖,通过抑制GSK-3β的活性,抑制NF-κB信号通路的激活,将HCT116细胞滞留在G1期。GABABR/GSK-3β/NF-κB信号通路可以作为临床预防和治疗结肠癌的潜在药物靶点之一。     

Ghrelin提高L6大鼠成肌细胞胰岛素敏感性及其机理

目的 研究Ghrelin对L6大鼠成肌细胞在棕榈酸诱导下的葡萄糖代谢和胰岛素敏感性的影响,并探讨其可能的机理。方法 培养L6大鼠成肌细胞,诱导分化后利用0.3 mmol/L的棕榈酸作用16 h,实验组加入不同剂量的Ghrelin （1、10和100 nmol/L）作用8 h,采用葡萄糖氧化酶-过氧化物酶法（GOD-POD）检测骨骼肌细胞对葡萄糖的摄取,并在荧光共聚焦显微镜下观察细胞膜葡萄糖转运因子-4 （GLUT-4）蛋白染色;采用免疫印迹（Western blot） 法检测骨骼肌细胞中总蛋白激酶B （Akt）、磷酸化蛋白激酶B （pAkt）、总糖原合成酶激酶-3β （GSK-3β）和磷酸化糖原合成酶激酶-3β （pGSK-3β）蛋白的表达。结果 Ghrelin使胰岛素抵抗之L6大鼠成肌细胞葡萄糖摄取量增加,细胞膜GLUT-4染色加深,pAkt及pGSK-3β蛋白表达增加（磷酸化表达增加）,而总Akt和总GSK-3β蛋白无明显变化,这种作用可被PI3K阻断剂（LY294002）消除。结论 Ghrelin通过磷酯酰肌醇-3激酶/蛋白激酶B/糖原合成酶激酶-3β （PI3K/Akt/GSK-3β）信号途径促进L6大鼠成肌细胞葡萄糖摄取量,从而提高L6大鼠成肌细胞胰岛素的敏感性。     

靶向糖原合成酶激酶-3β抗骨肉瘤的实验研究

 目的 研究糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)在骨肉瘤细胞增殖中的作用及相关分子机制,探讨其在骨肉瘤靶向治疗中的价值。方法 Western blot检测人成骨细胞及骨肉瘤细胞p-GSK-3β(Ser9)表达水平,观察GSK-3β抑制剂及siRNA干扰对细胞增殖、凋亡的影响,利用凋亡蛋白芯片筛查并验证GSK-3β调控骨肉瘤细胞的分子机制,通过裸鼠体内实验评估靶向GSK-3β对于骨肉瘤的治疗价值。结果 在骨肉瘤细胞中p-GSK-3β(Ser9)表达水平明显低于成骨细胞。GSK-3β特异性抑制剂及siRNA干扰均可明显抑制骨肉瘤细胞增殖并诱导凋亡蛋白cleave-caspase 3表达量明显上调。通过蛋白芯片筛查显示一组NF-κB调控的靶基因蛋白survivin、cIAP-1、XIAP及Bcl-2明显下调。Western blot验证了上述芯片结果,并发现氯化锂处理后p-IκBα水平下降,核内NF-κB p65表达量下降。NF-κB双荧光素酶报告系统检测稳定过表达持续活化GSK-3β细胞中NF-κB转录活性与空载体组细胞相比明显升高,而稳定干扰GSK-3β的细胞中NF-κB转录活性与空载体组细胞相比明显下降。裸鼠体内动物实验发现稳定干扰GSK-3β和采用氯化锂均可明显抑制骨肉瘤皮下移植瘤的生长。结论 GSK-3β在骨肉瘤中处于相对活化状态,可通过上调NF-κB转录活性调控骨肉瘤细胞增殖;靶向GSK-3β是骨肉瘤潜在的治疗新策略。     

GSK-3β抑制剂对糖尿病肾病大鼠的作用研究

目的:观察糖尿病肾病大鼠应用GSK-3β抑制剂(氯化锂)后生化指标、肾脏病理、肾组织磷酸化GSK-3β(p GSK-3β)与总糖原合成酶激酶-3β(GSK-3β)蛋白水平的比值,探讨GSK-3β抑制剂对糖尿病肾病的作用。方法:将50只雄性Wistar大鼠随机分为正常组(NC组)、单纯抑制剂组(NY组)、糖尿病肾病组(DN组)、DN后应用抑制剂组(DY组)。通过小剂量腹腔注射STZ联合高脂饮食建立DN大鼠模型;腹腔注射氯化锂进行干预。观察大鼠一般状态、血糖、血肌酐、尿蛋白等指标及肾组织病理变化;Western印迹方法检测肾组织总GSK-3β及p GSK-3β蛋白水平。结果:(1)与NC组相比,DN组及DY组大鼠24小时尿量、尿蛋白、血肌酐、血糖均升高;与DN组相比,DY组24 h尿蛋白定量下降。(2)与NC组相比,DN组肾脏病理呈糖尿病肾病样变化,DY组较DN组病理减轻。(3)NY组和NC组相比p GSK-3β/总GSK-3β蛋白水平差异无统计学意义;与NC组相比DN组及DY组p GSK-3β/总GSK-3β降低;DY组较DN组p GSK-3β/总GSK-3β增多。结论:氯化锂通过提高肾组织p GSK-3β蛋白表达量,抑制GSK-3β的活性,进而改善肾脏病理,减少尿蛋白,达到保护肾脏的作用。     

重组人红细胞生成素预处理对肾小管上皮细胞缺血再灌注损伤中PI3K-Akt-GSK-3β通路的调控作用

目的 探讨磷脂酰肌醇-3激酶（PI3K）-蛋白激酶B（Akt）-糖原合成酶激酶3β（GSK-3β）通路对人肾小管上皮细胞（HK-2）缺血再灌注（IR）损伤过程中细胞凋亡的调控及重组人红细胞生成素（rHuEPO）的保护作用。 方法 正常培养的HK-2细胞,分为7组：正常对照组、IR组、LY294002干预组（PI3K-Akt阻断剂,10 μmol/L）、LiCl干预组（GSK-3β阻断剂,20 μmol/L）、rHuEPO干预组（20 U/L）、rHuEPO+LY294002干预组、rHuEPO+LiCl干预组。Western印迹法检测Akt（Ser473）、GSK-3β（Ser9）及半胱氨酸天冬氨酸蛋白酶（caspase-3）活性; MTT法检测细胞活力;Annexin V和PI染色结合流式细胞仪技术检测细胞凋亡。 结果 IR损伤诱导HK-2细胞凋亡率上调（15.20%±1.43％）、Akt活性水平下降、GSK-3β及caspase-3酶活性水平上调,与正常对照组相比,差异有统计学意义（P < 0.05）。与IR组相比,LY294002干预使细胞凋亡率进一步上调（18.20%±2.06％）、Akt活性水平下调、GSK-3β及caspase-3酶活性上调,LiCl干预使细胞凋亡率下调（12.30%±0.85％）、Akt活性水平上调、GSK-3β及caspase-3酶活性下调,差异均有统计学意义（P < 0.05）。rHuEPO干预与IR组相比,细胞凋亡率下降（11.10%±1.62％）、Akt活性水平升高而GSK-3β及caspase-3酶活性下调,差异有统计学意义（P < 0.05）。与rHuEPO干预相比,rHuEPO+LY294002双干预细胞凋亡率升高（13.40%±1.94％）、Akt活性水平下降而GSK-3β及caspase-3酶活性上调,rHuEPO+LiCl双干预细胞凋亡率下调（7.50%±1.31％）、Akt活性水平上升而GSK-3β及caspase-3酶活性下降,差异均有统计学意义（P < 0.05）。 结论 IR损伤可引起肾小管上皮细胞凋亡,Akt活性降低及GSK-3β活性升高,影响caspase-3依赖的外源性凋亡途径可能是其凋亡机制之一。rHuEPO可通过增强Akt活性,降低GSK-3β及caspase-3酶活性,从而减轻细胞凋亡,对HK-2 IR损伤有一定的保护作用。     

GSK-3β在钙黏蛋白17介导的胃癌细胞侵袭中的作用及机制研究

目的:探讨GSK-3β在钙黏蛋白17(CDH17)介导的胃癌细胞侵袭中的作用及机制。方法:分别用CDH17 si RNA转染或GSK-3β抑制剂SB216763处理胃癌MKN-45细胞,以无处理和转染空载体的MKN-45细胞为空白对照及阴性对照,检测各组细胞GSK-3β、β-cantenin、NF-κB(p50/p65)的表达以及侵袭力变化。结果:与空白对照细胞比较,CDH17 si RNA转染后的MKN-45细胞CDH17、磷酸化GSK-3β、β-cantenin与p50/p65蛋白表达均明显降低,侵袭细胞数明显减少(均P0.05);SB216763处理后的MKN-45细胞CDH17与β-cantenin表达无明显变化(均P0.05),磷酸化GSK-3β与p50/p65表达明显降低,侵袭细胞数明显减少(均P0.05);转染空载体的MKN-45细胞各项指标均无明显变化(均P0.05)。结论:在CDH17介导的胃癌细胞侵袭信号通路中,GSK-3β可能处于β-cantenin下游,通过其磷酸化水平而调节NF-κB活性的关键分子。     

氯化锂预先给药对老龄大鼠腹部手术后认知功能的影响

目的 探讨氯化锂预先给药对老龄大鼠腹部手术后认知功能的影响.方法 雄性SD大鼠48只,18月龄,体重550～700 g,随机分为3组(n=16):对照组(C组)、手术组(O组)和氯化锂预处理组(L组).L组腹腔注射氯化锂2 mmol/kg,1次/d,连续7 d,C组和O组给予等容量生理盐水.给药结束后O组和L组行腹部手术,术后24 h时测定海马IL-1β含量、总糖原合成酶激酶3β(GSK-3β)和磷酸化GSK-3β(p-GSK-3β)的表达水平,术后4～6 d行Morris水迷宫实验(记录逃逸潜伏期和游泳距离).结果 与C组比较,O组术后4～6 d逃逸潜伏期和游泳距离延长,海马IL-1β含量升高,p-GSK-3β表达下调,L组术后4 d游泳距离延长,海马IL-1β含量降低(P＜0.05),O组和L组总GSK-3β表达差异无统计学意义(P＞0.05);与O组比较,L组逃逸潜伏期和游泳距离缩短,海马IL-1β含量降低,p-GSK-3β表达上调(P＜0.05),总GSK-3β表达差异无统计学意义(P＞0.05).结论 氯化锂预先给药可改善老龄大鼠术后认知功能,其机制与抑制海马GSK-3β的活性,减轻海马炎性反应有关.     

大鼠脊髓损伤后Wnt信号分子的表达变化

目的:探讨大鼠脊髓损伤后不同时期Wnt信号分子Wnt-1、β-连锁蛋白(β-catenin)及糖原合成酶激酶-3β(GSK-3β)在脊髓损伤局部的表达情况.方法:50只成年雌性SD大鼠随机均分为对照组和实验组,麻醉下手术显露T9～T11椎板,切除T10全椎板,实验组大鼠用NYU打击器以10g×5cm的打击能量致伤T10脊髓,对照组只行全椎板切除,不致伤脊髓.分别于术后1d、3d、5d、7d、14d每组各取5只大鼠,取以损伤区为中心共15mm范围内(对照组取相应部位)脊髓组织,提取总RNA,采用半定量RT-PCR的方法检测脊髓组织中Wnt-1、β-catenin及GSK-3β的mRNA表达量.结果:脊髓损伤后1d和3d时Wnt-1和β-catenin出现高表达,5d后其表达逐渐减弱,14d左右其表达基本恢复到正常水平,而在脊髓损伤后1d和3d时GSK-3β呈低表达,5d后其表达逐渐增强,各时间点之间差异有显著性(P<0.05).对照组中Wnt-1和β-catenin及GSK-3β均呈低表达,各时间点表达无显著差异(P<0.05).结论:大鼠脊髓损伤后损伤局部脊髓组织中Wnt-1,β-catenin及GSK-3β的表达发生变化,提示Wnt信号在脊髓损伤后的早期被激活,其可能与脊髓损伤后的修复再生有关.     

替米沙坦通过Wnt/β-catenin信号通路影响非小细胞肺癌A549细胞增殖、迁移和凋亡的研究

目的 研究替米沙坦对非小细胞肺癌A549细胞增殖、迁移和凋亡的影响,并探讨其机制.方法 体外培养非小细胞肺癌细胞株A549,采用CCK-8法检测不同浓度替米沙坦对A549细胞增殖活性的影响,以克隆形成实验检测不同浓度替米沙坦处理下A549的存活分数,以划痕实验检测不同浓度替米沙坦对A549细胞迁移能力的影响,Hoech...     

Glycogen synthase kinase 3 inhibitor attenuates endotoxin-induced liver injury

Background/Aims

Endotoxin (lipopolysaccharide, LPS)-induced acute liver injury was attenuated by endotoxin tolerance (ET), which is characterized by phosphatidylinositol 3-kinase pathway/Akt signaling. Glycogen synthase kinase 3 (GSK-3) acts downstream of phosphatidylinositol 3-kinase pathway/Akt and GSK-3 inhibitor protects against organic injury. This study evaluates the hypothesis that ET attenuated LPS-induced liver injury through inhibiting GSK-3 functional activity and downstream signaling.

Methods

Sprague-Dawley rats with or without low-dose LPS pretreatment were challenged with or without large dose of LPS and subsequently received studies. Serum tumor necrosis factor-alpha, interleukin-10, alanine aminotransferase, lactate dehydrogenase, and total bilirubin levels were analyzed, morphology of liver tissue was performed, glycogen content, myeloperoxidase content, phagocytosis activity of Kupffer cells, and the expression and inhibitory phosphorylation as well as kinase activity of GSK-3 were examined. Survival after LPS administration was also determined.

Results

LPS induced significant increases of serum TNF-α, alanine aminotransferase, lactate dehydrogenase, and total bilirubin (P < 0.05), which were companied by obvious alterations in liver: the injury of liver tissue, the decrease of glycogen, the infiltration of neutrophils, and the enhancement of phagocytosis of Kupffer cells (P < 0.05). LPS pretreatment significantly attenuated these alterations, promoted the inhibitory phosphorylation of GSK-3 and inhibited its kinase activity, and improved the survival rate (P < 0.05).

Conclusions

ET attenuated LPS-induced acute liver injury through inhibiting GSK-3 functional activity and its downstream signaling.     

PKB/Akt和GSK-3β在抗体介导的慢性排斥反应患者移植肾小管上皮细胞转分化中的作用

目的:观察磷酸化蛋白激酶B(p-Akt)、糖元合成激酶(GSK-3β)在抗体介导的慢性排斥反应(chronic active antibody-mediated reiection,ABMR)患者移植肾肾小管上皮细胞中的表达,探讨二者在移植肾小管上皮细胞转分化(EMT)中的作用。方法:38例移植肾穿刺标本经病理明确诊断为ABMR,按Banff 2009标准将其按间质纤维化/小管萎缩(IF/TA)程度Ⅰ、Ⅱ、Ⅲ级分为C1(n=12)、C2(n=14)、C3(n=12)组,用免疫组织化学技术和计算机真彩色图像分析系统半定量检测移植肾组织中p-Akt、GSK-3β、转化生长因子TGF-β_1、整合素连接激酶ILK、上皮细胞E-钙黏蛋白(E-cadherin)和α-平滑肌肌动蛋白(α-SMA)在各组中的表达面积,线性相关分别分析p-Akt、GSK-3β与转化生长因子TGF-β_1、整合素连接激酶ILK、E-cadherin和α-SMA表达的相关性及其与IF/TA病理分级之间的关系。9例正常肾组织作为对照组。结果:ABMR患者移植肾组织中p-AKt、GSK-3β、TGF-β_1、ILK和α-SMA的表达比正常肾组织明显增加(P <0. 001),并随(IF/TA)病理分级呈逐渐递增的趋势。E-钙黏蛋白在ABMR肾小管上皮细胞中的表达比正常肾组织明显减少(P <0. 001),组间呈递减趋势,移植肾组织中P-akt的表达与TGF-β_1、ILK和α-SMA呈正相关(r分别为0. 912、0. 871和0. 878,P <0. 001),而与E-cadherin的表达量呈负相关(r=-0. 849,P <0. 001);GSK-3β的表达与TGF-β_1、ILK、p-Akt和α-SMA呈正相关(r分别为0. 874、0. 793、0. 828、0. 781,P <0. 001),与E-cadherin的表达量呈负相关(r=-0. 781,P <0. 001)。p-Akt、GSK-3β、ILK、TGF-β_1和α-SMA的表达均与移植IF/TA程度呈正相关(r分别为0. 943、0. 863、0. 907、0. 964和0. 926,P <0. 001);而E-cadherin的表达与移植肾IF/TA程度成负相关(r=-0. 859,P <0. 001)。结论:P-Akt、GSK-3β作为TGF-β_1及ILK的重要下游细胞因子可能介导了ABMR所致的肾小管上皮细胞-肌成纤维细胞转分化的发生、发展,p-Akt和GSK-3β在ABMR所致移植肾间质纤维化进程中可能发挥重要作用。     

Glycogen synthase kinase 3β inhibition reduces mitochondrial oxidative stress in chronic myocardial ischemia

Objectives

Glycogen synthase kinase 3β (GSK-3β) inhibition has been reported to increase microvascular density and improve myocardial blood flow in a porcine model of chronic myocardial ischemia and metabolic syndrome. Inhibition of GSK-3β can also be cardioprotective by modulating fibrosis signaling and mitochondrial-induced apoptosis. We hypothesized GSK-3β inhibition would have a beneficial effect on myocardial fibrosis and oxidative stress in a porcine model of chronic myocardial ischemia and metabolic syndrome.

Role of glycogen synthase kinase 3β in protective effect of propofol against hepatic ischemia–reperfusion injury

Background

It was previously reported that propofol, an intravenously administered hypnotic and anesthetic agent, protects organs from ischemia–reperfusion (I/R) injury. However, the underlying mechanisms are largely unknown. Glycogen synthase kinase 3β (GSK-3β) is known to play an important role in the oxidative stress–induced apoptosis. In this study, we investigated the role of GSK-3β and mitochondrial permeability transition pore (MPTP) in the protective effects of propofol against hepatic I/R injury.

Materials and methods

The left and median hepatic artery and the portal vein branches were blocked by no-damage artery clips to create the model of partial ischemia (70%), and liver lobes were subjected to warm ischemia for 30, 60, 90 min, respectively. Reperfusion of 120 min was then initiated by the removal of clamp. The MPTP opening was assessed by measuring mitochondrial large amplitude swelling and mitochondrial membrane potential.

Results

Pretreatment with propofol in conditions of hepatic I/R inhibits the apoptosis of hepatocytes as evidenced by decreased terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells. Importantly, propofol suppressed the mitochondrial GSK-3β by promoting or preserving its phosphorylation at Ser9, thus restraining the opening of MPTP and preventing the mitochondrial swell and mitochondrial membrane potential collapse.

Conclusions

Propofol protects liver from I/R injury by sustaining the mitochondrial function, which is possibly involved with the modulation of MPTP and GSK-3β.     

Calpain inhibition modulates glycogen synthase kinase 3β pathways in ischemic myocardium: A proteomic and mechanistic analysis

Background

Calpain inhibition has an enhancing effect on myocardial perfusion and improves myocardial density by inhibiting glycogen synthase kinase 3β (GSK-3β) and up-regulating downstream signaling pathways, including the insulin/PI3K and WNT/β-catenin pathways, in a pig model of chronic myocardial ischemia in the setting of metabolic syndrome.

Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis

ObjectivesGlycogen synthase kinase (GSK)-3β, a serine/threonine protein kinase, has been implicated as a regulator of the inflammatory response. This study was performed to evaluate the effect of selective GSK-3β inhibitors in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA).MethodFLS from RA patients were treated with selective GSK-3β inhibitors, including lithium chloride, 6-bromoindirubin-3′-oxime (BIO), or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The effects of GSK-3β inhibition on pro-inflammatory mediators were determined by real-time PCR and ELISA. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 proteins were evaluated by western blot analysis. The in vivo effects of GSK-3β inhibitors were examined in mice with CIA.ResultsTreatment of RA FLS with GSK-3β inhibitors induced dose-dependent reductions in gene expression and the production of pro-inflammatory mediators. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 were decreased following treatment with GSK-3β inhibitors. GSK-3β inhibitors treatment attenuated clinical and histological severities of CIA in mice. Infiltration of T-cells, macrophages, and tartrate-resistant acid phosphatase positive cells was decreased in joint sections of CIA mice by GSK-3β inhibitors treatment. Serum levels of IL-1β, IL-6, TNF-α and IFN-γ in CIA mice were also significantly decreased in dose-dependent manners by treatment with GSK-3β inhibitors.ConclusionTreatment with GSK-3β inhibitors suppressed inflammatory responses in RA FLS and CIA mice. These findings suggest that the inhibition of GSK-3β can be used as an effective therapeutic agent for RA.