Th17细胞亚群在支气管哮喘中的发病机制及TLR2对Th17细胞分化的调控研究
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摘要
第一部分Th17和Tc17细胞亚群及其细胞因子白介素17在哮喘小鼠动物模型中的表达研究
【目的】探讨辅助性T细胞17(Th17)和CD8+IL-17+细胞(Tc17)在支气管哮喘小鼠中的比例变化及其意义。
【方法】24只BABL/c小鼠随机分成两组：哮喘组和正常对照组,每组12只,用卵蛋白(OVA)致敏和激发的方法建立小鼠哮喘模型。然后用流式细胞术检测脾脏单个核细胞中Th17细胞和Tc17细胞所占的百分比；用酶联免疫吸附试验(ELISA)检测支气管肺泡灌洗液中细胞因子IL-17的水平；双标免疫荧光检测肺组织中Th17细胞和Tc17细胞的表达。
【结果】哮喘组肺组织炎症改变明显；哮喘组脾脏细胞中Th17细胞比例显著高于对照组(P<0.0001),Tc17细胞比例与显著高于对照组(P<0.001)；哮喘组BALF中,IL-17水平显著高于正常对照组(P<0.001)；哮喘组BAL中细胞总数和嗜酸性粒细胞数目明显高于对照组(P<0.01)；肺组织免疫荧光结果示Th17细胞和Tc17细胞在哮喘小鼠的肺部有表达,主要分布在支气管周围和血管周围,并且数量明显高于对照组(P<0.01)。
【结论】哮喘小鼠的Th17细胞和Tc17细胞数量增多,并且分泌的细胞因子IL-17水平升高,而且哮喘小鼠肺部有较多的Th17细胞和Tc17细胞浸润,提示Th17细胞和Tc17细胞可能参与了哮喘的发病机制。
第二部分Toll样受体2信号对小鼠淋巴瘤EL4细胞系表达白细胞介素(IL)-17影响的研究
【目的】探讨TLR2信号通路对小鼠淋巴瘤细胞系EL4细胞表达分泌IL-17A的影响。
【方法】用ELISA法检测各组细胞上清液中IL-17A表达水平,实时荧光定量RT-PCR法检测各组细胞中RORyt和IL-17A的：mRNA的表达水平变化。
【结果】TLR2配体可以显著增加细胞IL-17A和RORyt和IL-17A的mRNA的表达,而TLR2抗体可以将这种促进作用抵消一部分,TLR2配体刺激后细胞上清中IL-17A蛋白水平也明显升高。
【结论】Toll样受体2信号对小鼠淋巴瘤EL4细胞系表达IL-17是起促进作用的,这种作用可能是通过促进转录因子RORyt的表达来实现的。
第三部分Toll样受体2信号激活对Th17细胞分化和功能的影响研究
【目的】探讨Toll样受体2信号在调节Th17细胞的分化和功能方面的作用,并且初步探讨参与调控的信号通路机制。
【方法】制作小鼠哮喘模型,免疫磁珠分选CD4+T细胞经体外诱导分化成Th17细胞,细胞分为四组：(1)空白对照组,(2)用TLR2的配体(LTA)激活TLR2信号组,(3)TLR2的抗体阻断TLR2信号组,(4)RORc基因的干扰慢病毒组。然后MTT法检测各组的细胞增殖情况,流式细胞仪检测各组胞内因子IL-17A的水平,ELISA检测各组的细胞上清液中的IL-17A蛋白水平,Real-time RT-PCR检测各组的Th17相关细胞因子(IL-17A、IL-17F和IL-22)的mRNA水平,并检测转录因子RORyt的mRNA水平的变化。
【结果】(1)MTT检测结果示,LTA、LTA+TLR2抗体和LTA+慢病毒都能增加Th17细胞的增殖,与空白对照组比较,P值的大小分别为P<0.05,P<0.001和P<0.01。(2)实时荧光定量PCR结果表明慢病毒感染细胞后可使RORc的mRNA水平下降86%,各组的Th17相关基因(?)nRNA水平检测,LTA组引起IL-17A、IL-17F和IL-22的mRNA水平明显升高(P<0.05),LTA+TLR2抗体组和LTA+慢病毒组上述升高效应又被逆转(P<0.05)。(3)蛋白水平检测胞内因子染色流式分析LTA可以明显刺激增加IL-17A+细胞的百分比,IL-17A+CD8-%由11.7%增加到22.5%(P<0.05)。ELISA检测细胞上清中的IL-17A结果为LTA组引起IL-17A蛋白水平增高(P<0.05),而LTA+TLR2抗体组和LTA+慢病毒组蛋白水平又下降(相比较与LTA组,P<0.05)。(4)TLR2信号对转录因子RORyt mRNA水平的影响：LTA组的RORyt mRNA水平明显增高(P<0.001)。
【结论】TLR2信号能促进Th17细胞的增殖,能增强Th17细胞的功能,并且是通过增加特异性的转录因子RORyt的表达来实现的。
第四部分支气管哮喘患者的血浆IL-21和总IgE水平及其相关性研究
【目的】探讨白介素-21(IL-21)和总IgE在支气管哮喘发病时的血清水平及其两者相关性。
【方法】随机收集哮喘急性发作期患者38例(急性发作组),哮喘缓解期患者23例(缓解组)和健康者19例(对照组)血清,用双抗体夹心酶联免疫吸附试验检测血清IL-21和总IgE水平
【结果】哮喘急性发作期患者血清IL-21水平明显高于正常对照组(P<0.05),急性发作期IL-21明显高于缓解期组(P<0.05),而缓解期和正常对照组差异无统计学意义。血清总IgE水平哮喘急性发作期和缓解期均明显高于正常对照组(P<0.05)。哮喘急性发作期血清IL-21水平和总IgE水平有显著负相关(r=-0.32,P<0.05)。【结论】IL-21可能通过调节IgE的分泌,在支气管哮喘的发病中发挥重要作用。
PartⅠChanges of the Ratio of T helper 17 cells and CD8+IL-17+T cells and the Level of Interleukin-17 in a Mouse Model of Asthma
【Objective】To investigate the changes of Th17 cells and Tc17 cells and the level of IL-17 in a mouse model of asthma.
【Methods】Twenty-four BABL/c mice were randomly divided into asthma group and control group. Mice were sensitized and challenged with ovalbumin(OVA) as asthmatic mouse models. The ratio of Th17 cells and Tcl7 cells in splenocytes was detected by flow cytometry. The level of IL-17 in bronchoalveolar lavage fluid(BALF) was determined by enzyme-linked immunosorbent assay(ELISA).The expression of Th17 cells and Tc17 cells in lungs was confirmed by double immunofluorescence.
【Results】The frequency of Thl7 cells and Tc17 cells in splenocytes from asthmatic mice were significantly higher than those of normal controls(P<0.0001 and P< 0.001, respectively); the level of cytokine IL-17 in BALF of asthmatic mice was more higher than those of normal controls(P<0.0001);the numbers of total cells and eosinophils in BAL were significantly higher than those of normal controls (both P<0.01).Th17 cells and Tc17 cells can be found in lung tissues of asthmatic mice, the numbers of these two kinds of cells were were significantly higher than those of normal controls (both P<0.01).
[Conclusion] Th17 cells and Tc17 cells may play an important role in the pathogenesis of asthma.
PartⅡToll-like Receptor 2 Signaling in EL4 T Cells Promotes the Expression of Interleukin-17
【Objective】To investigate the effect of toll-like receptor 2 signaling on the expression of interleukin-17 in EL4 T cell line.
【Methods】The RORγt and IL-17A mRNA expression were determined by real time RT-PCR, the expression of interleukin-17 protein were detected by ELISA.
[Results] The real time RT-PCR results suggest that TLR2 ligand treatment can significantly up-regulate expression of RORyt and IL-17A on mRNA level and on protein level.
【Conclusion】The toll-like receptor 2 signaling in EL4 cells can promote the expression of interleukin-17, this is probably dependent on up-regulating of the expression of the transcriptional factor RORyt.
PartⅢThe Differentiation and Function of T Helper 17 cells Promoted by Toll-like Receptor 2 Signaling in vitro via RORgammat pathway
【Objective】To investigate the role of toll-like receptor 2 signaling on the differentiation and function of Th17 cells.
【Methods】The CD4+T cells were isolated from spleens of asthmatic mice and purified by negative selection with a magnetic cell sort, then for Th17 differentiation, cells were cultured under Th17 condition(IL-6 and TGF-β1) for three days. Where indicated, LTA, TLR2 antibody and RORc-MR-lentivirus were added to cultures. Intracellular staining of cytokine IL-17A was analyzed by flow cytometry. IL-17A cytokine production was assessed by ELISA kits. For Th17 cell proliferation assays, we conducted MTT. Analyses of Th17-related genes(il-17a,il-17f,il-22 and rorc) transcripts were performed with real-time RT-PCR.
【Results】(1) Th17 cells proliferated more intensively where LTA was added in the media than those cultured without LTA(P<0.05,P<0.001 and P<0.01,respectively).(2) Fully differentiated Th17 cells treated with a TLR2 agonist LTA were found to produce increased amount of IL-17 proteins(P<0.05),and the neutralizing antibody for TLR2 can reverse the effects of LTA(P<0.05).(3)The results of intracellular staining of cytokine IL-17A showed that IL-17+cells were more dominant in LTA treated groups(from 11.7% up to 22.5%(P< 0.05).(4)Th17-associated mRNA(IL-17A、IL-17F and IL-22)were upregulated by a TLR2 agonist LTA (P<0.05),however,TLR2 antibody and RORc-MR-lentivirus can cancer out these effects(P< 0.05).
【Conclusion】TLR2 signaling can enhance Th17 differentiation and promote Th17 cell development.
Part IV The Interleukin-21 and Total Serum IgE Levels in Serum of Asthmatics and Their Correlation Analysis
【Objective】In order to investigate levels of interleukin-21 (IL-21) and total serum IgE in asthmatics,and to explore the relationship between IL-21 and total serum IgE in patients with allergic asthma.
【Methods】Totally 80 subjects were recruited and were divided into three groups:Control group(n=19),allergic asthma group (n=38) and controlled asthma group (n=23).The levels of IL-21 and total IgE in serum were detected by ELISA.
【Results】The IL-21 levels in serum control group,allergic asthma group and controlled asthma group were 17.19,21.99 pg/ml and 17.18 pg/ml, respectively.The levels of IL-21 were significantly different from each other between the control group and allergic asthma group (P<0.05).Negative relationship was found between the levels of IL-21 and total serum IgE in allergic asthma group (r=-0.32,P<0.05).
【Conclusion】Our results suggested that IL-21 might be involved in the pathogenesis of allergic asthma in human.
【目的】探讨辅助性T细胞17(Th17)和CD8+IL-17+细胞(Tc17)在支气管哮喘小鼠中的比例变化及其意义。
【方法】24只BABL/c小鼠随机分成两组：哮喘组和正常对照组,每组12只,用卵蛋白(OVA)致敏和激发的方法建立小鼠哮喘模型。然后用流式细胞术检测脾脏单个核细胞中Th17细胞和Tc17细胞所占的百分比；用酶联免疫吸附试验(ELISA)检测支气管肺泡灌洗液中细胞因子IL-17的水平；双标免疫荧光检测肺组织中Th17细胞和Tc17细胞的表达。
【结果】哮喘组肺组织炎症改变明显；哮喘组脾脏细胞中Th17细胞比例显著高于对照组(P<0.0001),Tc17细胞比例与显著高于对照组(P<0.001)；哮喘组BALF中,IL-17水平显著高于正常对照组(P<0.001)；哮喘组BAL中细胞总数和嗜酸性粒细胞数目明显高于对照组(P<0.01)；肺组织免疫荧光结果示Th17细胞和Tc17细胞在哮喘小鼠的肺部有表达,主要分布在支气管周围和血管周围,并且数量明显高于对照组(P<0.01)。
【结论】哮喘小鼠的Th17细胞和Tc17细胞数量增多,并且分泌的细胞因子IL-17水平升高,而且哮喘小鼠肺部有较多的Th17细胞和Tc17细胞浸润,提示Th17细胞和Tc17细胞可能参与了哮喘的发病机制。
第二部分Toll样受体2信号对小鼠淋巴瘤EL4细胞系表达白细胞介素(IL)-17影响的研究
【目的】探讨TLR2信号通路对小鼠淋巴瘤细胞系EL4细胞表达分泌IL-17A的影响。
【方法】用ELISA法检测各组细胞上清液中IL-17A表达水平,实时荧光定量RT-PCR法检测各组细胞中RORyt和IL-17A的：mRNA的表达水平变化。
【结果】TLR2配体可以显著增加细胞IL-17A和RORyt和IL-17A的mRNA的表达,而TLR2抗体可以将这种促进作用抵消一部分,TLR2配体刺激后细胞上清中IL-17A蛋白水平也明显升高。
【结论】Toll样受体2信号对小鼠淋巴瘤EL4细胞系表达IL-17是起促进作用的,这种作用可能是通过促进转录因子RORyt的表达来实现的。
第三部分Toll样受体2信号激活对Th17细胞分化和功能的影响研究
【目的】探讨Toll样受体2信号在调节Th17细胞的分化和功能方面的作用,并且初步探讨参与调控的信号通路机制。
【方法】制作小鼠哮喘模型,免疫磁珠分选CD4+T细胞经体外诱导分化成Th17细胞,细胞分为四组：(1)空白对照组,(2)用TLR2的配体(LTA)激活TLR2信号组,(3)TLR2的抗体阻断TLR2信号组,(4)RORc基因的干扰慢病毒组。然后MTT法检测各组的细胞增殖情况,流式细胞仪检测各组胞内因子IL-17A的水平,ELISA检测各组的细胞上清液中的IL-17A蛋白水平,Real-time RT-PCR检测各组的Th17相关细胞因子(IL-17A、IL-17F和IL-22)的mRNA水平,并检测转录因子RORyt的mRNA水平的变化。
【结果】(1)MTT检测结果示,LTA、LTA+TLR2抗体和LTA+慢病毒都能增加Th17细胞的增殖,与空白对照组比较,P值的大小分别为P<0.05,P<0.001和P<0.01。(2)实时荧光定量PCR结果表明慢病毒感染细胞后可使RORc的mRNA水平下降86%,各组的Th17相关基因(?)nRNA水平检测,LTA组引起IL-17A、IL-17F和IL-22的mRNA水平明显升高(P<0.05),LTA+TLR2抗体组和LTA+慢病毒组上述升高效应又被逆转(P<0.05)。(3)蛋白水平检测胞内因子染色流式分析LTA可以明显刺激增加IL-17A+细胞的百分比,IL-17A+CD8-%由11.7%增加到22.5%(P<0.05)。ELISA检测细胞上清中的IL-17A结果为LTA组引起IL-17A蛋白水平增高(P<0.05),而LTA+TLR2抗体组和LTA+慢病毒组蛋白水平又下降(相比较与LTA组,P<0.05)。(4)TLR2信号对转录因子RORyt mRNA水平的影响：LTA组的RORyt mRNA水平明显增高(P<0.001)。
【结论】TLR2信号能促进Th17细胞的增殖,能增强Th17细胞的功能,并且是通过增加特异性的转录因子RORyt的表达来实现的。
第四部分支气管哮喘患者的血浆IL-21和总IgE水平及其相关性研究
【目的】探讨白介素-21(IL-21)和总IgE在支气管哮喘发病时的血清水平及其两者相关性。
【方法】随机收集哮喘急性发作期患者38例(急性发作组),哮喘缓解期患者23例(缓解组)和健康者19例(对照组)血清,用双抗体夹心酶联免疫吸附试验检测血清IL-21和总IgE水平
【结果】哮喘急性发作期患者血清IL-21水平明显高于正常对照组(P<0.05),急性发作期IL-21明显高于缓解期组(P<0.05),而缓解期和正常对照组差异无统计学意义。血清总IgE水平哮喘急性发作期和缓解期均明显高于正常对照组(P<0.05)。哮喘急性发作期血清IL-21水平和总IgE水平有显著负相关(r=-0.32,P<0.05)。【结论】IL-21可能通过调节IgE的分泌,在支气管哮喘的发病中发挥重要作用。
PartⅠChanges of the Ratio of T helper 17 cells and CD8+IL-17+T cells and the Level of Interleukin-17 in a Mouse Model of Asthma
【Objective】To investigate the changes of Th17 cells and Tc17 cells and the level of IL-17 in a mouse model of asthma.
【Methods】Twenty-four BABL/c mice were randomly divided into asthma group and control group. Mice were sensitized and challenged with ovalbumin(OVA) as asthmatic mouse models. The ratio of Th17 cells and Tcl7 cells in splenocytes was detected by flow cytometry. The level of IL-17 in bronchoalveolar lavage fluid(BALF) was determined by enzyme-linked immunosorbent assay(ELISA).The expression of Th17 cells and Tc17 cells in lungs was confirmed by double immunofluorescence.
【Results】The frequency of Thl7 cells and Tc17 cells in splenocytes from asthmatic mice were significantly higher than those of normal controls(P<0.0001 and P< 0.001, respectively); the level of cytokine IL-17 in BALF of asthmatic mice was more higher than those of normal controls(P<0.0001);the numbers of total cells and eosinophils in BAL were significantly higher than those of normal controls (both P<0.01).Th17 cells and Tc17 cells can be found in lung tissues of asthmatic mice, the numbers of these two kinds of cells were were significantly higher than those of normal controls (both P<0.01).
[Conclusion] Th17 cells and Tc17 cells may play an important role in the pathogenesis of asthma.
PartⅡToll-like Receptor 2 Signaling in EL4 T Cells Promotes the Expression of Interleukin-17
【Objective】To investigate the effect of toll-like receptor 2 signaling on the expression of interleukin-17 in EL4 T cell line.
【Methods】The RORγt and IL-17A mRNA expression were determined by real time RT-PCR, the expression of interleukin-17 protein were detected by ELISA.
[Results] The real time RT-PCR results suggest that TLR2 ligand treatment can significantly up-regulate expression of RORyt and IL-17A on mRNA level and on protein level.
【Conclusion】The toll-like receptor 2 signaling in EL4 cells can promote the expression of interleukin-17, this is probably dependent on up-regulating of the expression of the transcriptional factor RORyt.
PartⅢThe Differentiation and Function of T Helper 17 cells Promoted by Toll-like Receptor 2 Signaling in vitro via RORgammat pathway
【Objective】To investigate the role of toll-like receptor 2 signaling on the differentiation and function of Th17 cells.
【Methods】The CD4+T cells were isolated from spleens of asthmatic mice and purified by negative selection with a magnetic cell sort, then for Th17 differentiation, cells were cultured under Th17 condition(IL-6 and TGF-β1) for three days. Where indicated, LTA, TLR2 antibody and RORc-MR-lentivirus were added to cultures. Intracellular staining of cytokine IL-17A was analyzed by flow cytometry. IL-17A cytokine production was assessed by ELISA kits. For Th17 cell proliferation assays, we conducted MTT. Analyses of Th17-related genes(il-17a,il-17f,il-22 and rorc) transcripts were performed with real-time RT-PCR.
【Results】(1) Th17 cells proliferated more intensively where LTA was added in the media than those cultured without LTA(P<0.05,P<0.001 and P<0.01,respectively).(2) Fully differentiated Th17 cells treated with a TLR2 agonist LTA were found to produce increased amount of IL-17 proteins(P<0.05),and the neutralizing antibody for TLR2 can reverse the effects of LTA(P<0.05).(3)The results of intracellular staining of cytokine IL-17A showed that IL-17+cells were more dominant in LTA treated groups(from 11.7% up to 22.5%(P< 0.05).(4)Th17-associated mRNA(IL-17A、IL-17F and IL-22)were upregulated by a TLR2 agonist LTA (P<0.05),however,TLR2 antibody and RORc-MR-lentivirus can cancer out these effects(P< 0.05).
【Conclusion】TLR2 signaling can enhance Th17 differentiation and promote Th17 cell development.
Part IV The Interleukin-21 and Total Serum IgE Levels in Serum of Asthmatics and Their Correlation Analysis
【Objective】In order to investigate levels of interleukin-21 (IL-21) and total serum IgE in asthmatics,and to explore the relationship between IL-21 and total serum IgE in patients with allergic asthma.
【Methods】Totally 80 subjects were recruited and were divided into three groups:Control group(n=19),allergic asthma group (n=38) and controlled asthma group (n=23).The levels of IL-21 and total IgE in serum were detected by ELISA.
【Results】The IL-21 levels in serum control group,allergic asthma group and controlled asthma group were 17.19,21.99 pg/ml and 17.18 pg/ml, respectively.The levels of IL-21 were significantly different from each other between the control group and allergic asthma group (P<0.05).Negative relationship was found between the levels of IL-21 and total serum IgE in allergic asthma group (r=-0.32,P<0.05).
【Conclusion】Our results suggested that IL-21 might be involved in the pathogenesis of allergic asthma in human.
引文
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