白细胞介素-2对前列腺增生上皮细胞增殖、凋亡及旁分泌的影响
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摘要
第一章前列腺增生上皮细胞中白细胞介素-2及其受体的表达
目的:炎症与良性前列腺增生(benign prostatic hyperplasia,BPH)关系密切,BPH组织中浸润的炎症细胞可产生大量白细胞介素-2(Interleukin-2,IL-2),IL-2及其受体在上皮细胞中表达增高,可能在BPH发生和发展中起重要作用。本研究拟探讨BPH组织中IL-2的表达及其与BPH合并炎症的病理组织学关系。观察人良性前列腺增生上皮细胞株BPH-1中白细胞介素-2受体(Interleukin-2 receptor,IL-2R)α、IL-2Rβ和IL-2Rγ的表达。
方法:应用免疫组织化学技术分别检测16例单纯BPH和42例合并炎症的BPH组织中IL-2蛋白的表达。采用逆转录聚合酶链式反应(RT-PCR)检测BPH-1细胞中IL-2Rα、IL-2Rβ和IL-2Rγ基因的表达;采用Western blot检测IL-2Rα、IL-2Rβ和IL-2Rγ蛋白的表达。
结果:(1)所有BPH组织均有IL-2蛋白表达,主要位于上皮细胞,在合并炎症的BPH中的表达显著高于单纯BPH。(2)RT-PCR结果表明BPH-1细胞表达IL-2Rα、IL-2Rβ和IL-2Rγ基因。(3)Westernblot检测到BPH-1细胞中IL-2Rα、IL-2Rβ和IL-2Rγ蛋白的表达。
结论:BPH组织中IL-2表达与浸润的炎症细胞有关。BPH-1细胞表达IL-2Rα、IL-2Rβ和IL-2Rγ,可作为一种较好的模型研究IL-2对BPH的影响。
第二章白细胞介素-2通过ERK1/2信号途径促进前列腺增生上皮细胞增殖
目的:研究人重组IL-2对BPH-1细胞增殖的作用及其信号转导途径。
方法:细胞增殖水平用MTT法检测。p-JNK,JNK,p-p38,p38,p-ERK1/2,ERK1/2用Western blot检测,联合ERK1/2信号转导阻断剂PD098059,p38信号转导阻断剂SB203580和JNK信号转导阻断剂SP600125干预,以探讨IL-2对BPH-1细胞增殖的信号转导机制。
结果:(1)MTT检测表明IL-2显著促进BPH-1细胞的增殖,且呈剂量依赖性。(2)IL-2干预诱导BPH-1细胞ERK1/2磷酸化。ERK1/2信号转导阻断剂PD098059能抑制IL-2促进BPH-1细胞增殖的作用,而p38信号转导阻断剂SB203580和JNK信号转导阻断剂SP600125无明显作用,说明ERK1/2在IL-2促进BPH-1细胞增殖中起关键作用。
结论:IL-2通过ERK1/2信号转导途径促进BPH-1细胞增殖。
第三章白细胞介素-2对前列腺增生上皮细胞凋亡及Bcl-2,Bax和Caspase-3蛋白表达的影响
目的:研究IL-2对BPH-1细胞凋亡及凋亡相关基因(Bcl-2,Bax,Caspase-3)表达的影响,探讨IL-2对BPH-1细胞凋亡的作用机制。
方法:细胞凋亡用吖啶橙/溴乙啶染色和酶联免疫吸附法(ELISA)检测。Bcl-2,Bax,Caspase-3蛋白表达用Western blot检测。
结果:(1)吖啶橙/溴乙啶染色和ELISA检测均表明,IL-2抑制BPH-1细胞凋亡,且呈时间及剂量依赖性。(2)IL-2干预可诱导Bcl-2蛋白表达,抑制Bax表达和Caspase-3的裂解活化。
结论:IL-2抑制BPH-1细胞凋亡与Bcl-2表达上调、Bax表达下调以及Caspase-3激活被抑制有关。
第四章白细胞介素-2通过调节前列腺增生上皮细胞的旁分泌抑制前列腺间质细胞分化
目的:前列腺间质和上皮细胞通过旁分泌和自分泌各种细胞因子相互影响。本研究观察IL-2对BPH-1细胞TGF-β1基因表达和TGF-β1蛋白分泌的影响,以及有无IL-2刺激的BPH-1条件培养液(conditioned medium,CM)对前列腺间质细胞分化的影响。
方法:采用RT-PCR测定BPH-1细胞TGF-β1基因的表达。酶联免疫吸附法(ELISA)检测BPH-1CM中TGF-β1水平。Western blot检测肌球蛋白重链(smooth muscle myosin heavy chain,SM-MHC)蛋白在前列腺间质细胞中的表达来判断间质细胞的分化。
结果:(1)IL-2抑制BPH-1细胞TGF-β1基因的表达(2)IL-2抑制BPH-1细胞TGF-β1的分泌。(3)BPH-1CM可促进前列腺间质细胞SM-MHC蛋白的表达,TGF-β1中和抗体能抑制该作用,而经过IL-2刺激的BPH-1CM抑制间质细胞SM-MHC蛋白的上调。
结论:IL-2可抑制BPH-1细胞TGF-β1的基因表达和蛋白分泌,从而间接抑制前列腺间质细胞的分化。
Chapter one
Interleukin-2 and Its Receptors Expression in Prostatic Epithelial Cells
Objective:Interleukin-2(IL-2) plays a significant role in benign prostatic hyperplasia(BPH).In the present study,the expression of IL-2 in BPH and its relationship with inflammation was firstly evaluated and then the expression of Interleukin-2 receptors(Rα,Rβ,Rγ) in human prostatic epithelial cell line BPH-1 was investigated.
Methods:The expression change of IL-2 protein in BPH specimens with or without inflammatory infiltrates was examined by immunohistochemistry.The expression of Interleukin-2 receptors(Rα, Rβ,Rγ) mRNA and protein in BPH-1 cells were determined by reverse transcription-polymerase chain reaction(RT-PCR) and Western blot.
Results:The expression of IL-2 was increased in BPH specimens with inflammatory infiltrates.Both Interleukin-2 receptors(Rα,Rβ,Rγ) mRNA and protein were expressed in BPH-1 cells.
Conclusions:IL-2 expression is associated with inflammatory pathology in BPH.Interleukin-2 receptors(Rα,Rβ,Rγ) are expressed in human prostatic epithelial cell line BPH-1.This cell line could be used for the investigation of the actions of IL-2 on prostatic epithelial cells.
Chapter two
Interleukin-2 Stimulates Proliferation of Prostatic Epithelial Cells through ERK1/2 Signal Pathway
Objective:To investigate the mechanism of IL-2 on the proliferation of human prostatic epithelial cell line BPH-1.
Methods:Cell proliferation was assessed by the MTT assay. Western blot was used to determine the status of activaton of ERK1/2, p38 and JNK.
Results:IL-2 stimulated proliferation of BPH-1 cells.IL-2 induced activation of ERK1/2,but not activation of p38 and JNK.PD098059, which is a selective ERK inhibitor,significantly inhibited IL-2-induced cell proliferation.
Conclusion:IL-2 can activate ERK1/2 pathway leading to proliferation of BPH-1 cells.
Chapter three
Effects of Interleukin-2 on Apoptosis and Bcl-2,Bax, Caspase-3 Expression in Prostatic Epithelial Cells
Objective:To investigate the effects of IL-2 on the apoptosis and the expression of apoptosis-related proteins(Bcl-2,Bax,Caspase-3) in human prostatic epithelial cell line BPH-1.
Methods:Cell apoptosis was analyzed by acidine orange/ethidium bromide staining and ELISA.The expression of Bcl-2,Bax and Caspase-3 were measured using Western blot.
Results:IL-2 inhibited BPH-1 cells apoptosis induced by serum deprivation in a dose- and time-dependent manner and decreased Caspase-3 activation.Under the treatment of IL-2,Western blot analysis showed an increased Bcl-2 protein and decreased Bax protein expression.
Conclusion:IL-2 can protect BPH-1 cells against apoptosis by regulating Bcl-2/Bax expression,and by blocking the activation of Caspase-3.
Chapter four
Interleukin-2 Inhibits Differentiation of Prostatic Stromal Cells through Regulation of Prostatic Epithelial Cells Paracrine
Objective:To characterize the effects of IL-2 on differentiation in stromal cells through regulation of human prostatic epithelial cell line BPH-1 paracrine.
Methods:BPH-1 cells were stimulated with different concentrations of IL-2.Conditioned medium(CM) were harvested and their effects on stromal cells were tested,mRNA of transforming growth factorβ1 (TGF-β1) was analyzed by RT-PCR.Western blot was used to determine smooth muscle myosin heavy chain(SM-MHC).ELISA was used to measure TGF-β1 protein secretion.
Results:IL-2 inhibited the mRNA expression and secretion of TGF-β1 in BPH-1 cells.A neutralizing antibody to TGF-β1 inhibited the stimulation of SM-MHC in stromal cells by BPH-1CM.The expression of SM-MHC decreased when stromal cells were cultured with CM harvested from IL-2 treated BPH-1 cells.
Conclusion:IL-2 inhibits differentiation of stromal cells by involving regulation of TGF-β1 expression and secretion.
目的:炎症与良性前列腺增生(benign prostatic hyperplasia,BPH)关系密切,BPH组织中浸润的炎症细胞可产生大量白细胞介素-2(Interleukin-2,IL-2),IL-2及其受体在上皮细胞中表达增高,可能在BPH发生和发展中起重要作用。本研究拟探讨BPH组织中IL-2的表达及其与BPH合并炎症的病理组织学关系。观察人良性前列腺增生上皮细胞株BPH-1中白细胞介素-2受体(Interleukin-2 receptor,IL-2R)α、IL-2Rβ和IL-2Rγ的表达。
方法:应用免疫组织化学技术分别检测16例单纯BPH和42例合并炎症的BPH组织中IL-2蛋白的表达。采用逆转录聚合酶链式反应(RT-PCR)检测BPH-1细胞中IL-2Rα、IL-2Rβ和IL-2Rγ基因的表达;采用Western blot检测IL-2Rα、IL-2Rβ和IL-2Rγ蛋白的表达。
结果:(1)所有BPH组织均有IL-2蛋白表达,主要位于上皮细胞,在合并炎症的BPH中的表达显著高于单纯BPH。(2)RT-PCR结果表明BPH-1细胞表达IL-2Rα、IL-2Rβ和IL-2Rγ基因。(3)Westernblot检测到BPH-1细胞中IL-2Rα、IL-2Rβ和IL-2Rγ蛋白的表达。
结论:BPH组织中IL-2表达与浸润的炎症细胞有关。BPH-1细胞表达IL-2Rα、IL-2Rβ和IL-2Rγ,可作为一种较好的模型研究IL-2对BPH的影响。
第二章白细胞介素-2通过ERK1/2信号途径促进前列腺增生上皮细胞增殖
目的:研究人重组IL-2对BPH-1细胞增殖的作用及其信号转导途径。
方法:细胞增殖水平用MTT法检测。p-JNK,JNK,p-p38,p38,p-ERK1/2,ERK1/2用Western blot检测,联合ERK1/2信号转导阻断剂PD098059,p38信号转导阻断剂SB203580和JNK信号转导阻断剂SP600125干预,以探讨IL-2对BPH-1细胞增殖的信号转导机制。
结果:(1)MTT检测表明IL-2显著促进BPH-1细胞的增殖,且呈剂量依赖性。(2)IL-2干预诱导BPH-1细胞ERK1/2磷酸化。ERK1/2信号转导阻断剂PD098059能抑制IL-2促进BPH-1细胞增殖的作用,而p38信号转导阻断剂SB203580和JNK信号转导阻断剂SP600125无明显作用,说明ERK1/2在IL-2促进BPH-1细胞增殖中起关键作用。
结论:IL-2通过ERK1/2信号转导途径促进BPH-1细胞增殖。
第三章白细胞介素-2对前列腺增生上皮细胞凋亡及Bcl-2,Bax和Caspase-3蛋白表达的影响
目的:研究IL-2对BPH-1细胞凋亡及凋亡相关基因(Bcl-2,Bax,Caspase-3)表达的影响,探讨IL-2对BPH-1细胞凋亡的作用机制。
方法:细胞凋亡用吖啶橙/溴乙啶染色和酶联免疫吸附法(ELISA)检测。Bcl-2,Bax,Caspase-3蛋白表达用Western blot检测。
结果:(1)吖啶橙/溴乙啶染色和ELISA检测均表明,IL-2抑制BPH-1细胞凋亡,且呈时间及剂量依赖性。(2)IL-2干预可诱导Bcl-2蛋白表达,抑制Bax表达和Caspase-3的裂解活化。
结论:IL-2抑制BPH-1细胞凋亡与Bcl-2表达上调、Bax表达下调以及Caspase-3激活被抑制有关。
第四章白细胞介素-2通过调节前列腺增生上皮细胞的旁分泌抑制前列腺间质细胞分化
目的:前列腺间质和上皮细胞通过旁分泌和自分泌各种细胞因子相互影响。本研究观察IL-2对BPH-1细胞TGF-β1基因表达和TGF-β1蛋白分泌的影响,以及有无IL-2刺激的BPH-1条件培养液(conditioned medium,CM)对前列腺间质细胞分化的影响。
方法:采用RT-PCR测定BPH-1细胞TGF-β1基因的表达。酶联免疫吸附法(ELISA)检测BPH-1CM中TGF-β1水平。Western blot检测肌球蛋白重链(smooth muscle myosin heavy chain,SM-MHC)蛋白在前列腺间质细胞中的表达来判断间质细胞的分化。
结果:(1)IL-2抑制BPH-1细胞TGF-β1基因的表达(2)IL-2抑制BPH-1细胞TGF-β1的分泌。(3)BPH-1CM可促进前列腺间质细胞SM-MHC蛋白的表达,TGF-β1中和抗体能抑制该作用,而经过IL-2刺激的BPH-1CM抑制间质细胞SM-MHC蛋白的上调。
结论:IL-2可抑制BPH-1细胞TGF-β1的基因表达和蛋白分泌,从而间接抑制前列腺间质细胞的分化。
Chapter one
Interleukin-2 and Its Receptors Expression in Prostatic Epithelial Cells
Objective:Interleukin-2(IL-2) plays a significant role in benign prostatic hyperplasia(BPH).In the present study,the expression of IL-2 in BPH and its relationship with inflammation was firstly evaluated and then the expression of Interleukin-2 receptors(Rα,Rβ,Rγ) in human prostatic epithelial cell line BPH-1 was investigated.
Methods:The expression change of IL-2 protein in BPH specimens with or without inflammatory infiltrates was examined by immunohistochemistry.The expression of Interleukin-2 receptors(Rα, Rβ,Rγ) mRNA and protein in BPH-1 cells were determined by reverse transcription-polymerase chain reaction(RT-PCR) and Western blot.
Results:The expression of IL-2 was increased in BPH specimens with inflammatory infiltrates.Both Interleukin-2 receptors(Rα,Rβ,Rγ) mRNA and protein were expressed in BPH-1 cells.
Conclusions:IL-2 expression is associated with inflammatory pathology in BPH.Interleukin-2 receptors(Rα,Rβ,Rγ) are expressed in human prostatic epithelial cell line BPH-1.This cell line could be used for the investigation of the actions of IL-2 on prostatic epithelial cells.
Chapter two
Interleukin-2 Stimulates Proliferation of Prostatic Epithelial Cells through ERK1/2 Signal Pathway
Objective:To investigate the mechanism of IL-2 on the proliferation of human prostatic epithelial cell line BPH-1.
Methods:Cell proliferation was assessed by the MTT assay. Western blot was used to determine the status of activaton of ERK1/2, p38 and JNK.
Results:IL-2 stimulated proliferation of BPH-1 cells.IL-2 induced activation of ERK1/2,but not activation of p38 and JNK.PD098059, which is a selective ERK inhibitor,significantly inhibited IL-2-induced cell proliferation.
Conclusion:IL-2 can activate ERK1/2 pathway leading to proliferation of BPH-1 cells.
Chapter three
Effects of Interleukin-2 on Apoptosis and Bcl-2,Bax, Caspase-3 Expression in Prostatic Epithelial Cells
Objective:To investigate the effects of IL-2 on the apoptosis and the expression of apoptosis-related proteins(Bcl-2,Bax,Caspase-3) in human prostatic epithelial cell line BPH-1.
Methods:Cell apoptosis was analyzed by acidine orange/ethidium bromide staining and ELISA.The expression of Bcl-2,Bax and Caspase-3 were measured using Western blot.
Results:IL-2 inhibited BPH-1 cells apoptosis induced by serum deprivation in a dose- and time-dependent manner and decreased Caspase-3 activation.Under the treatment of IL-2,Western blot analysis showed an increased Bcl-2 protein and decreased Bax protein expression.
Conclusion:IL-2 can protect BPH-1 cells against apoptosis by regulating Bcl-2/Bax expression,and by blocking the activation of Caspase-3.
Chapter four
Interleukin-2 Inhibits Differentiation of Prostatic Stromal Cells through Regulation of Prostatic Epithelial Cells Paracrine
Objective:To characterize the effects of IL-2 on differentiation in stromal cells through regulation of human prostatic epithelial cell line BPH-1 paracrine.
Methods:BPH-1 cells were stimulated with different concentrations of IL-2.Conditioned medium(CM) were harvested and their effects on stromal cells were tested,mRNA of transforming growth factorβ1 (TGF-β1) was analyzed by RT-PCR.Western blot was used to determine smooth muscle myosin heavy chain(SM-MHC).ELISA was used to measure TGF-β1 protein secretion.
Results:IL-2 inhibited the mRNA expression and secretion of TGF-β1 in BPH-1 cells.A neutralizing antibody to TGF-β1 inhibited the stimulation of SM-MHC in stromal cells by BPH-1CM.The expression of SM-MHC decreased when stromal cells were cultured with CM harvested from IL-2 treated BPH-1 cells.
Conclusion:IL-2 inhibits differentiation of stromal cells by involving regulation of TGF-β1 expression and secretion.
引文
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