β-arrestins在细胞凋亡和TLR4介导的先天性免疫反应中分子调控机制的研究
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摘要
目的:
研究β-arrestins在血清饥饿（SD）诱导的小鼠胚胎成纤维细胞（MEFs）凋亡中的作用，以及相关信号转导途径。
方法:
WT，β-arrestin1KO和β-arrestin2KOMEFs在无血清DMEM培养基中分别培养12h、24h、48h后，TUNEL检测细胞凋亡率。β-arrestin2KOMEFs转染β-arrestin2过表达质粒，转染48h后，SD诱导12h，24h、48h，TUNEL检测细胞凋亡情况。SD诱导12h、24h后，Westernblot检测WT，β-arrestin1KO和β-arrestin2KOMEFs内Caspase-3、ERK1/2、p38MAPKs、Akt蛋白的表达情况。
结果：
1.SD诱导不同时间后，β-arrestin1KO和β-arrestin2KOMEFs中凋亡细胞数目显著多于WTMEFs，并且在β-arrestin2KOMEFs中转染β-arrestin2质粒后能够明显减少细胞的凋亡。
2.SD诱导不同时间后，β-arrestin1KO和β-arrestin2KOMEFs中cleavedCaspase-3活性显著高于WTMEFs。
3.SD诱导不同时间后，β-arrestin1KO和β-arrestin2KOMEFs中p-ERK1/2、p-p38MAPKs水平显著高于WTMEFs，而p-Akt则明显低于WTMEFs。结论：
1.β-arrestin1和2能够显著减少SD诱导的MEFs的凋亡。
2.β-arrestin1和2通过调控促凋亡蛋白ERK1/2、p38MAPKs和抗凋亡蛋白Akt的信号途径参与SD介导的细胞凋亡信号通路的转导。
目的:
研究β-arrestins在脂多糖（LPS）、IL-1β诱导的MEFs、HEK293细胞炎症介质产生中的作用，以及相关信号转导途径。
方法:
LPS刺激WT，β-arrestin1/2DKOMEFs不同时间点后，RT-PCR测定细胞因子IL-6、IL-8和TNF-α的表达水平。β-arrestin1/2DKOMEFs分别转染β-arrestin1或β-arrestin2过表达质粒48h后，LPS刺激1h，RT-PCR及ELISA测定细胞因子IL-6、IL-8和TNF-α的表达水平，Westernblot测定细胞内ERK1/2、p38MAPKs、Akt的蛋白表达情况。IL-1β刺激HEK293细胞、转染了β-arrestin1或2过表达质粒的HEK293细胞及转染了β-arrestin1或2siRNA的HEK293细胞后，双荧光素酶报告基因检测转录因子NF-κB及AP-1的活性。
结果:
1.LPS刺激后，β-arrestin1/2DKOMEFs中IL-6、IL-8和TNF-α的表达水平显著高于WTMEFs，并且在β-arrestin1/2DKOMEFs中转染β-arrestin1或β-arrestin2质粒后能够明显减少IL-6、IL-8和TNF-α的表达水平。
2.LPS刺激后，β-arrestin1/2DKOMEFs中p-ERK1/2、p-p38MAPKs水平显著高于WTMEFs，转染β-arrestin1或β-arrestin2质粒后则能显著抑制p-ERK1/2、p-p38MAPKs的活性。
3.IL-1β刺激HEK293细胞后，能引起NF-κB及AP-1报告基因活性的增加，转染β-arrestin1或β-arrestin2质粒后能够抑制报告基因活性的增加。而转染了β-arrestin1或β-arrestin2siRNA后则能进一步增加NF-κB及AP-1报告基因活性。
结论:
1.β-arrestin1和2能够抑制LPS引起的细胞因子的表达，负调控TLR4介导的先天性免疫反应。
2.β-arrestin1和2是通过抑制ERK、p38MAPKs来负调控TLR4的信号通路。
3.β-arrestin1和2能够调控IL-1β引起的NF-κB及AP-1的激活
目的:
研究β-arrestin2在TLR4介导的小鼠肝脏缺血再灌注损伤中的保护作用及其可能机制。
方法:
C57BL/6β-arrestin2WT、KO雄性小鼠随机分为四组，两组对照组（WT、β-arrestin2KO）和两组实验组（IR+WT、IR+β-arrestin2KO）。制作小鼠肝脏热缺血再灌注模型，再灌注6小时后处死小鼠，检测肝脏功能、肝组织形态学、肝细胞凋亡、细胞因子、生存率等指标。Westernblot检测TLR4、Akt/GSK3β，Bcl-2家族，MAPKs及转录因子NF-κB的表达。
结果:
1.再灌注6小时，β-arrestin2KO组ALT、AST，细胞凋亡数目及细胞因子的产生显著高于WT组，β-arrestin2KO组小鼠生存率明显低于WT组。
2.Westernblot检测β-arrestin2KO组Akt/GSK、Bcl-2的活性显著低于WT组，而ERK1/2、p38MAPKs、NF-κB的活性高于WT组。
结论:
I/R后β-arrestin2通过调控Akt/GSK3β、MAPKs信号及影响转录因子NF-κB的活性，负调控TLR4的信号通路，保护I/R后肝组织的损伤。
Objective:
To detect the effect of β-arrestins on SD-induced apoptosis and signaling pathway in MEFs
Methods:
WT, β-arrestinl KO and β-arrestin2KO MEFs were cultured in DMEM medium without serum for12h、24h and48h, Apoptotic cells were determined by TUNEL assay. β-arrestin2full-length plasmid and control vector were transfected into β-arrestin2KO MEFs and then detected the cell apoptosis. Caspase-3, ERK1/2, p38MAPKs and Akt phosphory-lation were determined in WT,β-arrestinl and2KO MEFs following SD in a different time point by Westernblot.
Results:
1. Significantly greater cell apoptosis was observed when β-arrestinl or β-arrestin2deficient MEFs were exposed to SD than WT MEFs were exposed to SD. Moreover, transfection with β-arrestin2full-length plasmid strongly rescued the number of apoptosis in a deficiency of β-arrestin2MEFs.
2. The level of Caspase-3activation was significantly higher in the absence of β-arrestinl or2than in WT cells following SD treatment for12and24h.
3. The levels of phospho-ERK1/2and phospho-p38MAPKs were significantly higher in β-arrestinl or2KO MEFs than in WT MEFs. While the levels of phospho-Akt in β-arrestinl or2KO MEFs were significantly lower compared to in WT cells.
Conclusions:
1. β-arrestinl and β-arrestin2significantly inhibit MEFs apoptosis following SD
2.β-Arrestinl and β-arrestin2prevents cell apoptosis through pro-apoptotic ERKl/2and p38MAPKs and anti-apoptotic Akt pathways
Objective:
To detect the effect of β-arrestins on LPS、IL-1β-mediated the production of the cytokine and signaling pathway in MEFs and HEK293cells.
Methods:
RT-PCR analysis of relative IL-6、IL-8and TNF-a mRNA after LPS stimulation in WT and p-arrestinl/2DKO MEFs. p-arrestinl/2DKO MEFs were transfected with β-arrestinsl or β-arrestins2plasmid. Forty-eight hours posttransfection, cells were treated with or without LPS, mRNA and the concentration of IL-6、IL-8and TNF-a in culture supernatants were quantified by RT-PCR and ELISA, ERK1/2, p38MAPKs and Akt phosphorylation were determined by Westernblot. Dual-Luciferase reporter assay showing IL-1β-induced activation of transcription factor NF-κB and AP-1in HEK293cells.
Results:
1. Significantly increased production of IL-6、IL-8and TNF-a were dectected in β-arrestinl/2DKO MEFs than WT MEFs after LPS stimulation. Moreover, transfection with β-arrestinl or β-arrestin2full-length plasmid strongly reduced the producrion of IL-6、 IL-8and TNF-a in a deficiency of β-arrestinl/2MEFs.
2. The levels of phospho-ERK1/2and phospho-p38MAPKs were significantly higher in β-arrestinl/2DKO MEFs than in WT MEFs after LPS stimulation. While transfection with β-arrestinl or β-arrestin2full-length plasmid strongly decreased the activation of ERK1/2and p38MAPKs in β-arrestinl/2DKO MEFs compared to in WT cells.
3. IL-1β stimulation increased NF-κB and AP-1reported activity in HEK293cell-whereas transfection with β-arrestinl or β-arrestin2plasmid inhibit this increase.1 contrast, knockdown of β-arrestinl or β-arrestin2by siRNA increased the IL-1β-stimulated NF-κB and AP-1actication.
Conclusions:
1.β-arrestinl and β-arrestin2significantly inhibit the production of cytokine following LPS stimulation and negative regulate TLR4-mediated innate immune response.
2. β-Arrestinl and β-arrestin2negative regulate TLR4-mediated innate immune response through ERK1/2and p38MAPKs signaling pathways
3. β-Arrestinl and β-arrestin2inhibits IL-1β-induced NF-κB and AP-1activation.
Objective:
To determine the protection effect and possible mechanism of β-arrestin2in TLR4-mediated murine liver ischemia-reperfusion injury.
Methods:
C57BL/6β-arrestin2WT、KO male mice were randomly divided into four groups: control group (WT, β-arrestin2KO), experimental group (IR+WT, IR+β-arrestin2KO). Hepatic partial warm ischemia was performed for60minutes. After6h reperfusion, liver function, the degree of apoptosis, cytokine and the activation of TLR4、Akt/GSK3β, Bcl-2family, MAPKs, NF-κB were assessed. The survival rate was also investigated.
Results:
1. Serum ALT, AST, apoptotic cells and the production of cytokine were significantly higher in the I/R+P-arrestin2KO groups compared with those in WT group at6h after reperfusion. The survival rates of mice in I/R+P-arrestin2KO group significantly lower than in WT group.
2. The activation of Akt/GSK, Bcl-2significantly lower in I/R+β-arrestin2K group than in WT group. In contrast the levels of phospho-ERK1/2, phosphc p38MAPKs and NF-κB were significantly higher in I/R+β-arrestin2KO group than in WT group.
Conclusions:
β-arrestin2can negative regulate TLR4signaling and attenuate hepatocellular injury after hepatic warm I/R injury through Akt/GSK3β、 MAPKs and NF-κB signaling pathway.
研究β-arrestins在血清饥饿（SD）诱导的小鼠胚胎成纤维细胞（MEFs）凋亡中的作用，以及相关信号转导途径。
方法:
WT，β-arrestin1KO和β-arrestin2KOMEFs在无血清DMEM培养基中分别培养12h、24h、48h后，TUNEL检测细胞凋亡率。β-arrestin2KOMEFs转染β-arrestin2过表达质粒，转染48h后，SD诱导12h，24h、48h，TUNEL检测细胞凋亡情况。SD诱导12h、24h后，Westernblot检测WT，β-arrestin1KO和β-arrestin2KOMEFs内Caspase-3、ERK1/2、p38MAPKs、Akt蛋白的表达情况。
结果：
1.SD诱导不同时间后，β-arrestin1KO和β-arrestin2KOMEFs中凋亡细胞数目显著多于WTMEFs，并且在β-arrestin2KOMEFs中转染β-arrestin2质粒后能够明显减少细胞的凋亡。
2.SD诱导不同时间后，β-arrestin1KO和β-arrestin2KOMEFs中cleavedCaspase-3活性显著高于WTMEFs。
3.SD诱导不同时间后，β-arrestin1KO和β-arrestin2KOMEFs中p-ERK1/2、p-p38MAPKs水平显著高于WTMEFs，而p-Akt则明显低于WTMEFs。结论：
1.β-arrestin1和2能够显著减少SD诱导的MEFs的凋亡。
2.β-arrestin1和2通过调控促凋亡蛋白ERK1/2、p38MAPKs和抗凋亡蛋白Akt的信号途径参与SD介导的细胞凋亡信号通路的转导。
目的:
研究β-arrestins在脂多糖（LPS）、IL-1β诱导的MEFs、HEK293细胞炎症介质产生中的作用，以及相关信号转导途径。
方法:
LPS刺激WT，β-arrestin1/2DKOMEFs不同时间点后，RT-PCR测定细胞因子IL-6、IL-8和TNF-α的表达水平。β-arrestin1/2DKOMEFs分别转染β-arrestin1或β-arrestin2过表达质粒48h后，LPS刺激1h，RT-PCR及ELISA测定细胞因子IL-6、IL-8和TNF-α的表达水平，Westernblot测定细胞内ERK1/2、p38MAPKs、Akt的蛋白表达情况。IL-1β刺激HEK293细胞、转染了β-arrestin1或2过表达质粒的HEK293细胞及转染了β-arrestin1或2siRNA的HEK293细胞后，双荧光素酶报告基因检测转录因子NF-κB及AP-1的活性。
结果:
1.LPS刺激后，β-arrestin1/2DKOMEFs中IL-6、IL-8和TNF-α的表达水平显著高于WTMEFs，并且在β-arrestin1/2DKOMEFs中转染β-arrestin1或β-arrestin2质粒后能够明显减少IL-6、IL-8和TNF-α的表达水平。
2.LPS刺激后，β-arrestin1/2DKOMEFs中p-ERK1/2、p-p38MAPKs水平显著高于WTMEFs，转染β-arrestin1或β-arrestin2质粒后则能显著抑制p-ERK1/2、p-p38MAPKs的活性。
3.IL-1β刺激HEK293细胞后，能引起NF-κB及AP-1报告基因活性的增加，转染β-arrestin1或β-arrestin2质粒后能够抑制报告基因活性的增加。而转染了β-arrestin1或β-arrestin2siRNA后则能进一步增加NF-κB及AP-1报告基因活性。
结论:
1.β-arrestin1和2能够抑制LPS引起的细胞因子的表达，负调控TLR4介导的先天性免疫反应。
2.β-arrestin1和2是通过抑制ERK、p38MAPKs来负调控TLR4的信号通路。
3.β-arrestin1和2能够调控IL-1β引起的NF-κB及AP-1的激活
目的:
研究β-arrestin2在TLR4介导的小鼠肝脏缺血再灌注损伤中的保护作用及其可能机制。
方法:
C57BL/6β-arrestin2WT、KO雄性小鼠随机分为四组，两组对照组（WT、β-arrestin2KO）和两组实验组（IR+WT、IR+β-arrestin2KO）。制作小鼠肝脏热缺血再灌注模型，再灌注6小时后处死小鼠，检测肝脏功能、肝组织形态学、肝细胞凋亡、细胞因子、生存率等指标。Westernblot检测TLR4、Akt/GSK3β，Bcl-2家族，MAPKs及转录因子NF-κB的表达。
结果:
1.再灌注6小时，β-arrestin2KO组ALT、AST，细胞凋亡数目及细胞因子的产生显著高于WT组，β-arrestin2KO组小鼠生存率明显低于WT组。
2.Westernblot检测β-arrestin2KO组Akt/GSK、Bcl-2的活性显著低于WT组，而ERK1/2、p38MAPKs、NF-κB的活性高于WT组。
结论:
I/R后β-arrestin2通过调控Akt/GSK3β、MAPKs信号及影响转录因子NF-κB的活性，负调控TLR4的信号通路，保护I/R后肝组织的损伤。
Objective:
To detect the effect of β-arrestins on SD-induced apoptosis and signaling pathway in MEFs
Methods:
WT, β-arrestinl KO and β-arrestin2KO MEFs were cultured in DMEM medium without serum for12h、24h and48h, Apoptotic cells were determined by TUNEL assay. β-arrestin2full-length plasmid and control vector were transfected into β-arrestin2KO MEFs and then detected the cell apoptosis. Caspase-3, ERK1/2, p38MAPKs and Akt phosphory-lation were determined in WT,β-arrestinl and2KO MEFs following SD in a different time point by Westernblot.
Results:
1. Significantly greater cell apoptosis was observed when β-arrestinl or β-arrestin2deficient MEFs were exposed to SD than WT MEFs were exposed to SD. Moreover, transfection with β-arrestin2full-length plasmid strongly rescued the number of apoptosis in a deficiency of β-arrestin2MEFs.
2. The level of Caspase-3activation was significantly higher in the absence of β-arrestinl or2than in WT cells following SD treatment for12and24h.
3. The levels of phospho-ERK1/2and phospho-p38MAPKs were significantly higher in β-arrestinl or2KO MEFs than in WT MEFs. While the levels of phospho-Akt in β-arrestinl or2KO MEFs were significantly lower compared to in WT cells.
Conclusions:
1. β-arrestinl and β-arrestin2significantly inhibit MEFs apoptosis following SD
2.β-Arrestinl and β-arrestin2prevents cell apoptosis through pro-apoptotic ERKl/2and p38MAPKs and anti-apoptotic Akt pathways
Objective:
To detect the effect of β-arrestins on LPS、IL-1β-mediated the production of the cytokine and signaling pathway in MEFs and HEK293cells.
Methods:
RT-PCR analysis of relative IL-6、IL-8and TNF-a mRNA after LPS stimulation in WT and p-arrestinl/2DKO MEFs. p-arrestinl/2DKO MEFs were transfected with β-arrestinsl or β-arrestins2plasmid. Forty-eight hours posttransfection, cells were treated with or without LPS, mRNA and the concentration of IL-6、IL-8and TNF-a in culture supernatants were quantified by RT-PCR and ELISA, ERK1/2, p38MAPKs and Akt phosphorylation were determined by Westernblot. Dual-Luciferase reporter assay showing IL-1β-induced activation of transcription factor NF-κB and AP-1in HEK293cells.
Results:
1. Significantly increased production of IL-6、IL-8and TNF-a were dectected in β-arrestinl/2DKO MEFs than WT MEFs after LPS stimulation. Moreover, transfection with β-arrestinl or β-arrestin2full-length plasmid strongly reduced the producrion of IL-6、 IL-8and TNF-a in a deficiency of β-arrestinl/2MEFs.
2. The levels of phospho-ERK1/2and phospho-p38MAPKs were significantly higher in β-arrestinl/2DKO MEFs than in WT MEFs after LPS stimulation. While transfection with β-arrestinl or β-arrestin2full-length plasmid strongly decreased the activation of ERK1/2and p38MAPKs in β-arrestinl/2DKO MEFs compared to in WT cells.
3. IL-1β stimulation increased NF-κB and AP-1reported activity in HEK293cell-whereas transfection with β-arrestinl or β-arrestin2plasmid inhibit this increase.1 contrast, knockdown of β-arrestinl or β-arrestin2by siRNA increased the IL-1β-stimulated NF-κB and AP-1actication.
Conclusions:
1.β-arrestinl and β-arrestin2significantly inhibit the production of cytokine following LPS stimulation and negative regulate TLR4-mediated innate immune response.
2. β-Arrestinl and β-arrestin2negative regulate TLR4-mediated innate immune response through ERK1/2and p38MAPKs signaling pathways
3. β-Arrestinl and β-arrestin2inhibits IL-1β-induced NF-κB and AP-1activation.
Objective:
To determine the protection effect and possible mechanism of β-arrestin2in TLR4-mediated murine liver ischemia-reperfusion injury.
Methods:
C57BL/6β-arrestin2WT、KO male mice were randomly divided into four groups: control group (WT, β-arrestin2KO), experimental group (IR+WT, IR+β-arrestin2KO). Hepatic partial warm ischemia was performed for60minutes. After6h reperfusion, liver function, the degree of apoptosis, cytokine and the activation of TLR4、Akt/GSK3β, Bcl-2family, MAPKs, NF-κB were assessed. The survival rate was also investigated.
Results:
1. Serum ALT, AST, apoptotic cells and the production of cytokine were significantly higher in the I/R+P-arrestin2KO groups compared with those in WT group at6h after reperfusion. The survival rates of mice in I/R+P-arrestin2KO group significantly lower than in WT group.
2. The activation of Akt/GSK, Bcl-2significantly lower in I/R+β-arrestin2K group than in WT group. In contrast the levels of phospho-ERK1/2, phosphc p38MAPKs and NF-κB were significantly higher in I/R+β-arrestin2KO group than in WT group.
Conclusions:
β-arrestin2can negative regulate TLR4signaling and attenuate hepatocellular injury after hepatic warm I/R injury through Akt/GSK3β、 MAPKs and NF-κB signaling pathway.
引文
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