GATA3-NFAT1相互作用在人T细胞IL-13基因表达中作用的研究
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摘要
支气管哮喘是一种严重危害人类健康的常见病,多发病。目前认为,支气管哮喘是以气道可逆性阻塞、高反应性和气道炎症为特征的一组综合征,气道炎症是前两者的基础。在多种遗传和环境因素共同作用下,经过巨噬细胞(包括树突状细胞)的抗原呈递作用,Na(?)ve T辅助细胞(Th 0)被活化,分化为Th 2细胞,释放IL-4、IL-5、IL-13等多种Th 2细胞因子,促进了支气管哮喘的形成和发展。其中IL-13是一种重要的Th2细胞因子,它通过诱导哮喘气道炎症、增加气道高反应性、促进粘液分泌,并参与了哮喘气道重建,成为支气管哮喘发病机制中的重要介质。但迄今为止,对IL-13基因表达的分子调控机制仍知之甚少。
T细胞是产生IL-13的主要来源。CD3/CD28双信号通路对T细胞的刺激能够模拟T细胞在体内受抗原活化产生Th2细胞因子的过程。转录因子在基因的表达和调控上具有核心作用,GATA3是Th2细胞特异性的转录因子,细胞中增高的GATA3能够同时促进Th2细胞中IL-4、IL-5和IL-13的基因表达。许多研究表明在IL-13基因启动子区域GATA位点对IL-13的基因表达起重要作用。活化T细胞核因子(nuclear factor of activated T cell,NFAT)是TCR介导的信号转导通路中关键的转录因子。我们的前期研究表明在CD3/CD28双信号通路刺激后NFAT1与IL-13启动子结合增强。在人IL-13基因启动子区域GATA3与NFAT1位点邻近,作为同时参与IL-13基因转录的GATA3和NFAT1间是否存在相互作用?如何相互作用?均值得进一步探讨。本课题通过研究T细胞经CD3/CD28活化后观察GATA3和NFAT1在IL-13启动子区域功能上的相互作用,探索IL-13基因转录的分子机制,并进一步研究糖皮质激素丙酸氟替卡松(Fluticasonepropionate,FP)和传统哮喘治疗药物三氧化二砷(Arsenic Troxide,AT)对该相互作用的影响。
第一部分GATA3-NFAT1相互作用在人活化T细胞IL-13基因表达中的作用
目的:研究T细胞在CD3/CD28双信号通路共刺激活化后,细胞内GATA3与NFAT1的结合情况及NFAT1抑制剂FK-506对GATA3与IL-13启动子结合的影响,探讨GATA3-NFAT1相互作用在T细胞IL-13基因表达中的作用。
方法:采用CD3/CD28单克隆抗体(浓度分别为10μg/ml和5μg/ml)双信号通路对Hut-78细胞进行共刺激,分别在0min、30min、1h、2h时采用免疫共沉淀(IP)的方法观察GATA3与N-FAT1结合情况及FK-506对两者结合的影响。通过染色质免疫共沉淀(CHIP)的方法研究NFAT1被FK-506阻断后GATA3与IL-13启动子区域的结合情况。
结果:Hut-78细胞在CD3/CD28共刺激活化后,细胞内NFAT1和GATA3结合增强,在刺激30min时两者即有结合,随着刺激时间的延长在1h、2h时两者结合有进一步增强的趋势,呈明显的时间依赖性。FK-506(1n M)组在30min、1h、2h时均能抑制NFAT1与GATA3的结合,以2h时抑制更为明显(2.25±0.1 VS 1.18±0.09),P＜0.05。用FK-506对NFATl进行抑制后,GATA3与IL-13的启动子区域结合减弱。T细胞经CD3/CD28免疫共刺激活化30分钟时FK-506抑制GATA3与IL-13启动子结合的作用不明显,而在1h时能够抑制GATA3同IL-13启动子的结合(3.95±0.26 VS 2.82±0.44),2h时这种抑制效应更为明显,其抑制效应约为50%(4.34±1.42 VS 1.73±0.09),P＜0.05。
结论:T细胞经过CD3/CD28共刺激活化后细胞内NFAT1和GATA3结合增强,FK-506能抑制两者的结合。FK-506能抑制GATA3与IL-13启动子区域结合。FK-506可能通过影响两者的结合,抑制了GATA3对IL-13基因转录的启动。
第二部分:FP抑制活化T细胞IL-13基因表达的机制
目的:研究T细胞在CD3/CD28共刺激活化后,FP对NFAT1和GATA3结合的影响及FP对GATA3与IL-13启动子结合的影响,探讨FP抑制活化T细胞中IL-13基因表达的可能机制。
方法:采用CD3/CD28单克隆抗体(浓度分别为10μg/ml和5gg/ml)双信号通路对Hut-78细胞进行共刺激,分别在0min、30min、1h、2h时采用免疫共沉淀(IP)的方法观察GATA3与NFAT1结合情况及FP对两者结合的影响。通过染色质免疫共沉淀(CHIP)的方法研究FP对GATA3与IL-13启动子结合的影响。
结果:与对照组相比,经CD3/CD28刺激组GATA3与NFAT1结合增强,且在30min、1h、2h各时间点逐渐增高,呈时间依赖性。FP(10~(-8)M)能够部分抑制GATA3与NFAT1的结合,在细胞活化30min(1.33±0.08VS 0.91±0.083)、1h(1.97±0.18 VS 1.56±0.13)、2h(2.65±0.18 VS 1.80±0.23)时FP均可抑制两者的结合(P＜0.05)。HUT-78细胞经CD3/CD28双信号通路共刺激活化后在30min、1h及2h各时间点GATA-3与IL-13启动子区域结合逐渐增强。FP在细胞活化1h能显著抑制GATA3与IL-13启动子区域结合(8.19±2.1 8 VS 2.69±1.33),P＜0.05。
结论:T细胞经过CD3/CD28活化后GATA3与NFAT1结合增强,并促进GATA3与IL-13启动子区域结合。FP可能部分通过影响GATA3和NFAT1的相互作用,抑制T细胞IL-13基因表达。
第三部分:砷剂对活化T细胞IL-13基因表达的影响
目的:研究T细胞在CD3/CD28双信号通路刺激后IL-13的基因表达以及三氧化二砷对该基因表达的影响,并探讨三氧化二砷(AT)抑制IL-13基因表达的可能机制。
方法:采用CD3/CD28单克隆抗体(浓度分别为10μg/ml和5μg/ml)双信号通路对Hut-78细胞进行共刺激,在30min及19h时用RT-PCR方法观察IL-13mRNA表达及AT对IL-13mRNA表达的影响,并采用IP方法观察在细胞活化0min、30min、1h、2h时GATA3与NFAT1结合情况及AT对两者结合的影响。
结果:CD3/CD28双信号通路共刺激后,Hut-78细胞的IL-13mRNA表达增加,在19h时砷剂(5μM)能够明显抑制该基因的表达(6.77±2.78 VS 2.24±0.57),P＜0.05。Hut-78细胞在经过CD3/CD28免疫活化30分钟后,GATA3和NFATl两者即有结合且在2小时内两者结合呈逐渐增强趋势,AT在2h时能够部分抑制两者的结合(2.47±1.83VS 1.41±1.11,P＜0.05。
结论:对Th2细胞IL-13基因转录表达的抑制可能是AT平喘抗炎的机制之一,该过程可能是通过部分抑制GATA3和NFAT1两者相互作用实现的。
Asthma is a complex inflammatory disease of the lung characterized by airway hyperresponsiveness(AHR),eosinophilic inflammation and mucus hypersecretion.The inflammatory process,which is the basis of AHR and mucus hypersecretion,is believed to be a result of inappropriate immune responses to common aeroallergens in genetically susceptible individuals. It has been hypothesized that CD4~+T cells that produce a Th2 pattern of cytokines(IL-4,IL-5,IL-13)play a pivotal role in the pathogenesis of asthma.However,the therapy targeted at IL-4 and IL-5 proved little efficacy.IL-13 has been recognized as a critical regulator of the allergic response.Blockade of IL-13 markedly inhibits allergen-induced airway eosinophilia,hyperresponsiveness,mucus production and airway remodeling.However,the molecular mechanisms regulating IL-13 production are still largely unknown.GATA3 and NFAT1 both play an important role in the expression of IL-13 gene.To investigate the interaction between GATA3 and NFAT1 on IL-13 gene expression,human T cell lines(Hut-78 cells)were stimulated with anti-CD3 and anti-CD28 antibodies to mimic antigen-mediated co-stimulation in vivo.
PARTⅠ:The synergistic interaction between NFAT1 and GATA3 On gene expression of IL-13 in human T cells
Objective:To investigate the synergistic interaction between NFAT1 and GATA3 on IL-13 gene expression in human T cells due to CD3/CD28 co-stimulation.
Methods:Hut-78 cells were stimulated with anti-CD3/CD28 monoclonal antibodies at the concentration of 10μg/ml and 5μg/ml respectively.The interaction between NFAT1 and GATA3 in several times(0min,30min, 1h,2h)was detected by immunoprecipitation assays.Chromatin immunoprecipitation assays were used to investigate the binding of GATA3 to the promoter of IL-13.
Results:Anti-CD3/CD28 co-stimulation induced the binding of GATA3 and NFAT1 in a time-dependant manner.FK-505 can inhibit the binding of GATA3 to NFAT1,and thus the binding of GATA3 to IL- 13 promoter.
Conclusions:These results demonstrate the important role of the synergistic interaction between NFAT1 and GATA3 in the regulation of IL-13 gene expression in Hut-78 cells following CD3/CD28 co-stimulation.
PARTⅡ:The role of FP on the gene expression of IL-13 in actived human T cells
Objective:To study the effect of FP on the GATA3-NFAT1 interaction and subsequent GATA3 binding to IL-13 promoter in human T cells due to CD3/CD28 co-stimulation and investigate the anti-inflammatory mechanism of FP.
Methods:Hut-78 cells were stimulated with anti-CD3/CD28 monoclonal antibodies at the concentration of 10μg/ml and 5μg/ml respectively.The effect of FP on the GATA3-NFAT1 interaction in 0min,30min,1h and 2h were detected by immunoprecipitation assays.Chromatin immunoprecipitation assays were used to investigate the binding of GATA3 to the promoter of IL- 13.
Results:Anti-CD3/CD28 co-stimulation induced the binding of GATA3 and NFAT1 in a time-dependant manner,which was partially inhibited by FP at the concentration of 10~(-8)M FP also inhibited the binding of GATA3 to the promoter of IL- 13.
Conclusions:FP can inhibit IL-13 gene expression in actived human T cells,which may be associated with inhibiting of the formation of GATA3-NFAT1 compound and the binding of GATA3 to the promoter of IL-13.
PARTⅢ:Arsenic trioxide inhibits the gene expression of IL-13 in activated T cells
Objective:To study the interleukin 13(IL-13)gene expression in T cells due to CD3/CD28 co-stimulation and the effect of arsenic trioxide(AT) on IL-13 gene expression.
Methods:Hut-78 cells were stimulated with anti-CD3/CD28 monoclonal antibodies(10μg/ml and 5μg/ml,respectively).IL-13 mRNA level in Hut-78 cells was measured in groups with or without AT treatment.The effect of AT on the GATA3-NFAT1 compound in 0min,30min,1h and 2h were detected by immunoprecipitation assays.
Results:The level of IL-13 mRNA increased in Hut-78 cells due to CD3/CD28 co-stimulation.However AT inhibited the gene expression of IL-13.AT inhibited the binding of GATA3 and NFAT1 in actived human T cells in 2h.
Conclusions:AT would inhibit the gene expression of IL-13 in activated T cells,which might be partially through inhibiting the formation of the GATA3-NFAT1 compound.
T细胞是产生IL-13的主要来源。CD3/CD28双信号通路对T细胞的刺激能够模拟T细胞在体内受抗原活化产生Th2细胞因子的过程。转录因子在基因的表达和调控上具有核心作用,GATA3是Th2细胞特异性的转录因子,细胞中增高的GATA3能够同时促进Th2细胞中IL-4、IL-5和IL-13的基因表达。许多研究表明在IL-13基因启动子区域GATA位点对IL-13的基因表达起重要作用。活化T细胞核因子(nuclear factor of activated T cell,NFAT)是TCR介导的信号转导通路中关键的转录因子。我们的前期研究表明在CD3/CD28双信号通路刺激后NFAT1与IL-13启动子结合增强。在人IL-13基因启动子区域GATA3与NFAT1位点邻近,作为同时参与IL-13基因转录的GATA3和NFAT1间是否存在相互作用?如何相互作用?均值得进一步探讨。本课题通过研究T细胞经CD3/CD28活化后观察GATA3和NFAT1在IL-13启动子区域功能上的相互作用,探索IL-13基因转录的分子机制,并进一步研究糖皮质激素丙酸氟替卡松(Fluticasonepropionate,FP)和传统哮喘治疗药物三氧化二砷(Arsenic Troxide,AT)对该相互作用的影响。
第一部分GATA3-NFAT1相互作用在人活化T细胞IL-13基因表达中的作用
目的:研究T细胞在CD3/CD28双信号通路共刺激活化后,细胞内GATA3与NFAT1的结合情况及NFAT1抑制剂FK-506对GATA3与IL-13启动子结合的影响,探讨GATA3-NFAT1相互作用在T细胞IL-13基因表达中的作用。
方法:采用CD3/CD28单克隆抗体(浓度分别为10μg/ml和5μg/ml)双信号通路对Hut-78细胞进行共刺激,分别在0min、30min、1h、2h时采用免疫共沉淀(IP)的方法观察GATA3与N-FAT1结合情况及FK-506对两者结合的影响。通过染色质免疫共沉淀(CHIP)的方法研究NFAT1被FK-506阻断后GATA3与IL-13启动子区域的结合情况。
结果:Hut-78细胞在CD3/CD28共刺激活化后,细胞内NFAT1和GATA3结合增强,在刺激30min时两者即有结合,随着刺激时间的延长在1h、2h时两者结合有进一步增强的趋势,呈明显的时间依赖性。FK-506(1n M)组在30min、1h、2h时均能抑制NFAT1与GATA3的结合,以2h时抑制更为明显(2.25±0.1 VS 1.18±0.09),P＜0.05。用FK-506对NFATl进行抑制后,GATA3与IL-13的启动子区域结合减弱。T细胞经CD3/CD28免疫共刺激活化30分钟时FK-506抑制GATA3与IL-13启动子结合的作用不明显,而在1h时能够抑制GATA3同IL-13启动子的结合(3.95±0.26 VS 2.82±0.44),2h时这种抑制效应更为明显,其抑制效应约为50%(4.34±1.42 VS 1.73±0.09),P＜0.05。
结论:T细胞经过CD3/CD28共刺激活化后细胞内NFAT1和GATA3结合增强,FK-506能抑制两者的结合。FK-506能抑制GATA3与IL-13启动子区域结合。FK-506可能通过影响两者的结合,抑制了GATA3对IL-13基因转录的启动。
第二部分:FP抑制活化T细胞IL-13基因表达的机制
目的:研究T细胞在CD3/CD28共刺激活化后,FP对NFAT1和GATA3结合的影响及FP对GATA3与IL-13启动子结合的影响,探讨FP抑制活化T细胞中IL-13基因表达的可能机制。
方法:采用CD3/CD28单克隆抗体(浓度分别为10μg/ml和5gg/ml)双信号通路对Hut-78细胞进行共刺激,分别在0min、30min、1h、2h时采用免疫共沉淀(IP)的方法观察GATA3与NFAT1结合情况及FP对两者结合的影响。通过染色质免疫共沉淀(CHIP)的方法研究FP对GATA3与IL-13启动子结合的影响。
结果:与对照组相比,经CD3/CD28刺激组GATA3与NFAT1结合增强,且在30min、1h、2h各时间点逐渐增高,呈时间依赖性。FP(10~(-8)M)能够部分抑制GATA3与NFAT1的结合,在细胞活化30min(1.33±0.08VS 0.91±0.083)、1h(1.97±0.18 VS 1.56±0.13)、2h(2.65±0.18 VS 1.80±0.23)时FP均可抑制两者的结合(P＜0.05)。HUT-78细胞经CD3/CD28双信号通路共刺激活化后在30min、1h及2h各时间点GATA-3与IL-13启动子区域结合逐渐增强。FP在细胞活化1h能显著抑制GATA3与IL-13启动子区域结合(8.19±2.1 8 VS 2.69±1.33),P＜0.05。
结论:T细胞经过CD3/CD28活化后GATA3与NFAT1结合增强,并促进GATA3与IL-13启动子区域结合。FP可能部分通过影响GATA3和NFAT1的相互作用,抑制T细胞IL-13基因表达。
第三部分:砷剂对活化T细胞IL-13基因表达的影响
目的:研究T细胞在CD3/CD28双信号通路刺激后IL-13的基因表达以及三氧化二砷对该基因表达的影响,并探讨三氧化二砷(AT)抑制IL-13基因表达的可能机制。
方法:采用CD3/CD28单克隆抗体(浓度分别为10μg/ml和5μg/ml)双信号通路对Hut-78细胞进行共刺激,在30min及19h时用RT-PCR方法观察IL-13mRNA表达及AT对IL-13mRNA表达的影响,并采用IP方法观察在细胞活化0min、30min、1h、2h时GATA3与NFAT1结合情况及AT对两者结合的影响。
结果:CD3/CD28双信号通路共刺激后,Hut-78细胞的IL-13mRNA表达增加,在19h时砷剂(5μM)能够明显抑制该基因的表达(6.77±2.78 VS 2.24±0.57),P＜0.05。Hut-78细胞在经过CD3/CD28免疫活化30分钟后,GATA3和NFATl两者即有结合且在2小时内两者结合呈逐渐增强趋势,AT在2h时能够部分抑制两者的结合(2.47±1.83VS 1.41±1.11,P＜0.05。
结论:对Th2细胞IL-13基因转录表达的抑制可能是AT平喘抗炎的机制之一,该过程可能是通过部分抑制GATA3和NFAT1两者相互作用实现的。
Asthma is a complex inflammatory disease of the lung characterized by airway hyperresponsiveness(AHR),eosinophilic inflammation and mucus hypersecretion.The inflammatory process,which is the basis of AHR and mucus hypersecretion,is believed to be a result of inappropriate immune responses to common aeroallergens in genetically susceptible individuals. It has been hypothesized that CD4~+T cells that produce a Th2 pattern of cytokines(IL-4,IL-5,IL-13)play a pivotal role in the pathogenesis of asthma.However,the therapy targeted at IL-4 and IL-5 proved little efficacy.IL-13 has been recognized as a critical regulator of the allergic response.Blockade of IL-13 markedly inhibits allergen-induced airway eosinophilia,hyperresponsiveness,mucus production and airway remodeling.However,the molecular mechanisms regulating IL-13 production are still largely unknown.GATA3 and NFAT1 both play an important role in the expression of IL-13 gene.To investigate the interaction between GATA3 and NFAT1 on IL-13 gene expression,human T cell lines(Hut-78 cells)were stimulated with anti-CD3 and anti-CD28 antibodies to mimic antigen-mediated co-stimulation in vivo.
PARTⅠ:The synergistic interaction between NFAT1 and GATA3 On gene expression of IL-13 in human T cells
Objective:To investigate the synergistic interaction between NFAT1 and GATA3 on IL-13 gene expression in human T cells due to CD3/CD28 co-stimulation.
Methods:Hut-78 cells were stimulated with anti-CD3/CD28 monoclonal antibodies at the concentration of 10μg/ml and 5μg/ml respectively.The interaction between NFAT1 and GATA3 in several times(0min,30min, 1h,2h)was detected by immunoprecipitation assays.Chromatin immunoprecipitation assays were used to investigate the binding of GATA3 to the promoter of IL-13.
Results:Anti-CD3/CD28 co-stimulation induced the binding of GATA3 and NFAT1 in a time-dependant manner.FK-505 can inhibit the binding of GATA3 to NFAT1,and thus the binding of GATA3 to IL- 13 promoter.
Conclusions:These results demonstrate the important role of the synergistic interaction between NFAT1 and GATA3 in the regulation of IL-13 gene expression in Hut-78 cells following CD3/CD28 co-stimulation.
PARTⅡ:The role of FP on the gene expression of IL-13 in actived human T cells
Objective:To study the effect of FP on the GATA3-NFAT1 interaction and subsequent GATA3 binding to IL-13 promoter in human T cells due to CD3/CD28 co-stimulation and investigate the anti-inflammatory mechanism of FP.
Methods:Hut-78 cells were stimulated with anti-CD3/CD28 monoclonal antibodies at the concentration of 10μg/ml and 5μg/ml respectively.The effect of FP on the GATA3-NFAT1 interaction in 0min,30min,1h and 2h were detected by immunoprecipitation assays.Chromatin immunoprecipitation assays were used to investigate the binding of GATA3 to the promoter of IL- 13.
Results:Anti-CD3/CD28 co-stimulation induced the binding of GATA3 and NFAT1 in a time-dependant manner,which was partially inhibited by FP at the concentration of 10~(-8)M FP also inhibited the binding of GATA3 to the promoter of IL- 13.
Conclusions:FP can inhibit IL-13 gene expression in actived human T cells,which may be associated with inhibiting of the formation of GATA3-NFAT1 compound and the binding of GATA3 to the promoter of IL-13.
PARTⅢ:Arsenic trioxide inhibits the gene expression of IL-13 in activated T cells
Objective:To study the interleukin 13(IL-13)gene expression in T cells due to CD3/CD28 co-stimulation and the effect of arsenic trioxide(AT) on IL-13 gene expression.
Methods:Hut-78 cells were stimulated with anti-CD3/CD28 monoclonal antibodies(10μg/ml and 5μg/ml,respectively).IL-13 mRNA level in Hut-78 cells was measured in groups with or without AT treatment.The effect of AT on the GATA3-NFAT1 compound in 0min,30min,1h and 2h were detected by immunoprecipitation assays.
Results:The level of IL-13 mRNA increased in Hut-78 cells due to CD3/CD28 co-stimulation.However AT inhibited the gene expression of IL-13.AT inhibited the binding of GATA3 and NFAT1 in actived human T cells in 2h.
Conclusions:AT would inhibit the gene expression of IL-13 in activated T cells,which might be partially through inhibiting the formation of the GATA3-NFAT1 compound.
引文
1.Maziak W.The Th1-Th2 paradigm and asthma.J asthma。2003;40(2):201-5.
2.Wills-Karp M,Luyimbazi J,Xu X,et al.Interleukin-13:central mediator of allergic asthma.Science.1998;282(5397):2258-61.
3.Wilson MS,Elnekave E,Mentink-Kane MM et al.IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation,airway-hyperreactivity,and fibrosis in mice.J Clin Invest.2007;117(10):2941-51
4.Zheng W and Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Cell.1997;89(4):587-96.
5.Pai SY,Truitt ML,Ho IC.GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells.Proc Natl Acad Sci U S A.2004;101(7):1993-8.
6.Feske S,Giltnane J,Dolmetsh R,et al.Gene regulation mediated by calcium signals in T lymphocytes.Nat Immunol.2001;(4)2:316-24.
7.Ogawa K,Kaminuma O,Okudaira H,et al.Transcriptional regulation of the IL-5 gene in peripheral T cells of asthmatic patients.Clin Exp Immunol.2002;130(3):475-83
8.Xin Y,Lee KY,Jazrawi EP,et al.The expression of IL-13 gene is regulated by NFAT1 in HUT-78 cells.Eur Respir J.2005;26:232s.
9.国家卫生部新闻办公室《2OO5世界哮喘日通知》及相关附件2005年4月30日
10.Wills-Karp M,Luyimbazi J,Xu X,et al.Interleukin-13:central mediator of allergic asthma.Science.1998;282(5397):2258-61.
11.Zimmerman N,Hershey GK,Foster PS,et al.Chemokines in asthma.Cooperative interaction between chemokines and IL-13.J Allergy Clin Immunol.2003;111(2):227-42.
12.Richter A,Puddicombe SM,Lordan JL,et al.The contribution of IL-4and IL-13 to the epithelial-mesenchymal trophic unit in asthma.Am J Respir Cell Mol Biol.2001;25(3):385-91.
13.Mackenzie AN,Li X,Largaespada DA,et al.Structural comparion and chromosomal localization of the human and the mouse IL-13genes.J Immunol, 1993; 150(12):5436-44.
14. Merika M and Orkin SH.DNA-binding specificity of GATA family transcription factors. Mol Cell Biol. 1993;13(7):3999-4010
15. Yamashita M, Ukai-Tadenuma M, Miyamoto T, et al. Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci. J Biol Chem. 2004 ;279(26):26983-90
16. Kishikawa H, Sun J, Choi A, et al. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. J Immunol. 2002; 167(8):4414-20.
17. Hogan PG, Chen L, Nardone J, et al. Transcriptional regulation by calcium, calcineurin and NFAT. Gen Dev. 2003; 17(18):2205-32.
18. Shaw KT, Ho AM, Raghavan A, et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci USA. 1995; 92(24): 11205-9.
19. Monticelli S and Rao A. NFAT1 and NFAT2 are positive regulator of IL-4 gene transcription. Eur J Immunol .2002; 32(10):2971-8.
20. Tjian R, Maniatis T. Transcriptional activation: a complex puzzle with few easy pieces. Cell. 1994 ;77(1):5-8
21. Maneechotesuwan K, X Yao, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol. 2007; 178(4):2491-8.
22. Diedrichs H, Hagemeister J, Chi M, et al. Activation of the cal-cineurin/NFAT signalling cascade starts early in human hypertrophic myocardium. J Int Med Res. 2007;35(6):803-18
23. Agarwal S, Avni O, Rao A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity. 2000; 12(6):643-52.
24.Yamashita M,Ukai-Tadenuma M,Miyamoto T,et al.Essential role of GATA3 for the maintenance of type 2 helper T(Th2)cytokine production and chromatin remodeling at the Th2 cytokine gene loci.J Biol Chem.2004;279(26):26983-90
25.Wang J,Shannon MF,Young IG.A role for Ets1,synergizing with AP-1 and GATA-3 in the regulation of IL-5 transcription in mouse Th2 lymphocytes.Int Immunol.2006;18(2):313-23.
26.Masuda A,Yoshikai Y,Kume H,et al.The interaction between GATA proteins and activator protein-1 promotes the transcription of IL-13 in mast cells.J Immunol.2004;173(9):5564-73.
1. Fireman P. Understanding asthma pathophysiology. Allergy Asthma Proc. 2003;24(2):79-83
2. Nakajima H, Takatsu K. Role of cytokines in allergic airway inflammation. Int Arch Allergy Immunol. 2007;142(4):265-73
3. Di Lorenzo G, Pacor ML, Pellitteri ME, Gangemi S et al.In vitro effects of fluticasone propionate on IL-13 production by mito-gen-stimulated lymphocytes . Mediators Inflamm. 2002 ;11(3):187-90
4. Pai SY, Truitt ML, Ho IC. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci USA. 2004; 101(7):1993-8.
5. Feske S, Giltnane J, Dolmetsh R, et al. Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. 2001 ;2 (4) :316-24.
6. Perretti M, D'Acquisto F. Novel aspects of annexin 1 and glucocorti-coid biology: intersection with nitric oxide and the lipoxin receptor. Inflamm Allergy Drug Targets. 2006; 5(2):107-14.
7. Chiang BT, Liu YW, Chen BK, et al. Direct interaction of C/EBPdelta and Sp1 at the GC-enriched promoter region synergizes the IL-10 gene transcription in mouse macrophage. J Biomed Sci. 2006; 13(5):621-35.
8. Bhavsar P, Ahmad T and Adcock IM. The role of histone deacetylases in asthma and allergic diseases. J Allergy Clin Immunol. 2008 ; 121(3): 580-4.
9. Adcock IM, Tsaprouni L, Bhavsar P, et al. Epigenetic regulation of airway inflammation. Curr Opin Immunol. 2007; 19(6):694-700.
10. Ito K, Charron CE and Adcock IM. Impact of protein acetylation in inflammatory lung diseases. Pharmacol Ther. 2007; 116(2):249-65.
11.Bilodeau S, Vallette-Kasic S, Gauthier Y, et al. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006; 20(20):2871-86.
12. Necela BM, Cidlowski JA. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. The American Thoracic society.2004; l(3):239-46.
13. Maneechotesuwan K, X Yao, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol 2007; 178(4):2491-98.
14. Ogata k, Sato K and Tahirov. Eukarykotic transcriptional regulatory complexes: cooperativity from near and afar. Curropin in Stru Biol.2003; 13(1):40-8.
1.Fireman P.Understanding asthma pathophysiology.Allergy Asthma Proc.2003;24(2):79-83
2.Haller JS.Therapeutic mule:the use of arsenic in the nineteeth century material medica.Parmacy in History,1975;17(3):87-100.
3.殷凯生,姚欣,陈俊娣等.在实验动物中砷剂平喘机制的研究[J]南京医科大学学报,1999,19(5):433-4.
4.丁礼仁,沈华浩,崔巍.砷剂对支气管哮喘大鼠气道炎症的影响.中华结核和呼吸杂志;2002,25(11):686-7.
5.Ngoc PL,Gold DR,Tzianabos AO,et al.Cytokines,allergy,and asthma.Curr Opin Allergy Clin Immunol.2005;5(2):161-6.
6.Wills-Karp M,Luyimbazi J,Xu X,et al.Interleukin-13:central mediator of allergic asthma.Science.1998;(282):2258-61.
7.Wilson MS,Elnekave E,Mentink-Kane MM,et al.IL-13Ralpha2and IL-10 coordinately suppress airway inflammation,air way-hyperreactivity,and fibrosis in mice.J Clin Invest.2007;117(10):2941-51
8.Mackenzie AN,Li X,Largaespada DA,et al.structural comparion and chromosomal Localization of the human and the mouse IL-13gene.J Immunal 1993,150(12):5436-44
9.Blanchard C,Mishra A,Saito H,et al.Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody.Clin Exp Allergy.2005,35(8):1104-11.
10.Hirst SJ,Hallsworth MP,Peng QI,et al.Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1B and is mediated by the interleukin-4 receptor αchain.Am J Respir Crit Care Med,2002,165(8):1161-71.
11.Laoukili J,Perret E,Willems T,et al.IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells.Clin Invest,2001,108(12):1817-24.
12.Yamashita N,Tashimo H,Ishida Y,et al.Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness.Am J Physiol Lung Cell Mol Physiol.2006,290(6):1045-51.
13. Laporte JC, Moore PE, Baraldo S, et al. Direct effects of inter-leukin-13 on signaling pathways for physiologic responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med, 2001, 164(1): 141-8.
14. Booth BW, Sandifer T, Martin LD , et al.IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17. Respir Res,2007,8(1) :48-51.
15. Maneechotesuwan K, Xin Y, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. Immunol 2007, 178(4):2491-8.
16. Macian F. NFAT proteins: key regulators of T-cell development and Function. Nat Rev Immunol. 2005; 5(6):472-84.
17. Xin Y, Lee KY, Jazrawi EP, et al. The expression of interleukin-13 gene is regulated by NFAT1 in Hut-78 cells. Eur Respir J. 2005,26(8):232-4.
1.Mackenzie AN,Li X,Largaespada DA,et al.structural comparion and chromosomal localization of the human and the mouse IL-13genes J Immunal,1993,150(12):5436-44.
2. Songyang, Z., S. E. Shoelson, M. Chaudhuri, et al . SH2 domains recognize specific phosphopeptide sequences. Cell 1993 (72):767.
3. Fichtner-Feigl S, Strober W, Kawakami K,et al.Interleukin-13 signaling through the IL-13α2receptor is involved in induction of TGF-β1 production and fibrosis. Nat Med. 2006 Jan;12(1):99-106.
4. Kishikawa H, Sunday J, Choi A, et al. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. [J] J Immunol. 2002;(167):4414-20.
5. Faith A, Richards DF, Verhoef A, et al. Impaired secretion ofmter-leukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy. [J] Clin Exp Allergy. 2003;(33):1209-15
6. Wills-Karp M, Luyimbazi J, Xu X, etal.Interleukin-13:central mediator of allergic asthma. Science. 1998;(282):2258-61.
7. Venkayya R, Lam M, Willkom M, et al. The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsive-ness through direct effects on resident airway cells. Am J Respir Cell Mol Biol. 2002(26):202-08.
8. Grunstein MM, Hakonarson H, Leiter J, et al. IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2002(282):L520-28.
9. Li L, Xia Y, Nguyen A, et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelialcells. J Immunol. 1999(162):2477-87.
10. Zimmerman N, Hershey GK, Foster PS, Rothenberg ME. Chemokines in asthma, cooperative interaction between chemoki-nes and IL-13. J Allergy Clin Immunol 2003(111):227-242.
11. Aliman MZ , Piazza FM , selby DM , et al . Muc25/5al mucin-messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. Am J Respir Cell Mol Biol ,2002 ,(22): 253-260.
12. Danahay H, Atherton H, Jones G, Bridges RJ, Poll CT. Inter-leukin-13 induces a hypersecretory ion transport phenotype in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2002 (282) :L226 -L236.
13. Pope SM, Brandt EB, Mishra A, et al. IL-13 induces eosinophil recruitment into the lung by an IL-5 and eotaxin-dependent mechanism. J Allergy Clin Immunol. 2001; 108:594-601.
14. Zimmermann N, et al. Dissection ofexperimental asthma with DNA microarray analysis identifies arginase in asthma pathogene-sis. J Clin Invest 2003(111): 1863 -1874.
15. Richter A, Puddicombe SM, Lordan JL, et al. The contribution of interleukin (IL) -4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir CellMolBio2001(25):385-91.
16. Wen FQ, Kohyama T, Liu X, et al. Interleukin-4- and interleukin-13-enhanced transforming growth factor beta-2 production in cultured human bronchial epithelial cells is attenuated by inter-feron-gamma. Am J Respir Cell Mol Biol. 2002(26):484-90.
17. Esp inosa K,Bosse Y, Stankova J, et al. CysLTl recep tor up regulationby TGF-beta and IL-13 is associated with bronchial smooth muscle cell p roliferation in response to LTD4 [J]. J A llergy Clin Imm unol,2003, 111 (5): 1032-1040
18.Kumar RK,Herbert C,Foster PS.Expression of growth factors by air-way ep ithelial cells in a model of chronic asthma:regulation and relationship to subep ithelial fibrosis[J].Clin Exp A llergy,2004,34(4):567-575.
2.Wills-Karp M,Luyimbazi J,Xu X,et al.Interleukin-13:central mediator of allergic asthma.Science.1998;282(5397):2258-61.
3.Wilson MS,Elnekave E,Mentink-Kane MM et al.IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation,airway-hyperreactivity,and fibrosis in mice.J Clin Invest.2007;117(10):2941-51
4.Zheng W and Flavell RA.The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Cell.1997;89(4):587-96.
5.Pai SY,Truitt ML,Ho IC.GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells.Proc Natl Acad Sci U S A.2004;101(7):1993-8.
6.Feske S,Giltnane J,Dolmetsh R,et al.Gene regulation mediated by calcium signals in T lymphocytes.Nat Immunol.2001;(4)2:316-24.
7.Ogawa K,Kaminuma O,Okudaira H,et al.Transcriptional regulation of the IL-5 gene in peripheral T cells of asthmatic patients.Clin Exp Immunol.2002;130(3):475-83
8.Xin Y,Lee KY,Jazrawi EP,et al.The expression of IL-13 gene is regulated by NFAT1 in HUT-78 cells.Eur Respir J.2005;26:232s.
9.国家卫生部新闻办公室《2OO5世界哮喘日通知》及相关附件2005年4月30日
10.Wills-Karp M,Luyimbazi J,Xu X,et al.Interleukin-13:central mediator of allergic asthma.Science.1998;282(5397):2258-61.
11.Zimmerman N,Hershey GK,Foster PS,et al.Chemokines in asthma.Cooperative interaction between chemokines and IL-13.J Allergy Clin Immunol.2003;111(2):227-42.
12.Richter A,Puddicombe SM,Lordan JL,et al.The contribution of IL-4and IL-13 to the epithelial-mesenchymal trophic unit in asthma.Am J Respir Cell Mol Biol.2001;25(3):385-91.
13.Mackenzie AN,Li X,Largaespada DA,et al.Structural comparion and chromosomal localization of the human and the mouse IL-13genes.J Immunol, 1993; 150(12):5436-44.
14. Merika M and Orkin SH.DNA-binding specificity of GATA family transcription factors. Mol Cell Biol. 1993;13(7):3999-4010
15. Yamashita M, Ukai-Tadenuma M, Miyamoto T, et al. Essential role of GATA3 for the maintenance of type 2 helper T (Th2) cytokine production and chromatin remodeling at the Th2 cytokine gene loci. J Biol Chem. 2004 ;279(26):26983-90
16. Kishikawa H, Sun J, Choi A, et al. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. J Immunol. 2002; 167(8):4414-20.
17. Hogan PG, Chen L, Nardone J, et al. Transcriptional regulation by calcium, calcineurin and NFAT. Gen Dev. 2003; 17(18):2205-32.
18. Shaw KT, Ho AM, Raghavan A, et al. Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells. Proc Natl Acad Sci USA. 1995; 92(24): 11205-9.
19. Monticelli S and Rao A. NFAT1 and NFAT2 are positive regulator of IL-4 gene transcription. Eur J Immunol .2002; 32(10):2971-8.
20. Tjian R, Maniatis T. Transcriptional activation: a complex puzzle with few easy pieces. Cell. 1994 ;77(1):5-8
21. Maneechotesuwan K, X Yao, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol. 2007; 178(4):2491-8.
22. Diedrichs H, Hagemeister J, Chi M, et al. Activation of the cal-cineurin/NFAT signalling cascade starts early in human hypertrophic myocardium. J Int Med Res. 2007;35(6):803-18
23. Agarwal S, Avni O, Rao A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity. 2000; 12(6):643-52.
24.Yamashita M,Ukai-Tadenuma M,Miyamoto T,et al.Essential role of GATA3 for the maintenance of type 2 helper T(Th2)cytokine production and chromatin remodeling at the Th2 cytokine gene loci.J Biol Chem.2004;279(26):26983-90
25.Wang J,Shannon MF,Young IG.A role for Ets1,synergizing with AP-1 and GATA-3 in the regulation of IL-5 transcription in mouse Th2 lymphocytes.Int Immunol.2006;18(2):313-23.
26.Masuda A,Yoshikai Y,Kume H,et al.The interaction between GATA proteins and activator protein-1 promotes the transcription of IL-13 in mast cells.J Immunol.2004;173(9):5564-73.
1. Fireman P. Understanding asthma pathophysiology. Allergy Asthma Proc. 2003;24(2):79-83
2. Nakajima H, Takatsu K. Role of cytokines in allergic airway inflammation. Int Arch Allergy Immunol. 2007;142(4):265-73
3. Di Lorenzo G, Pacor ML, Pellitteri ME, Gangemi S et al.In vitro effects of fluticasone propionate on IL-13 production by mito-gen-stimulated lymphocytes . Mediators Inflamm. 2002 ;11(3):187-90
4. Pai SY, Truitt ML, Ho IC. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci USA. 2004; 101(7):1993-8.
5. Feske S, Giltnane J, Dolmetsh R, et al. Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. 2001 ;2 (4) :316-24.
6. Perretti M, D'Acquisto F. Novel aspects of annexin 1 and glucocorti-coid biology: intersection with nitric oxide and the lipoxin receptor. Inflamm Allergy Drug Targets. 2006; 5(2):107-14.
7. Chiang BT, Liu YW, Chen BK, et al. Direct interaction of C/EBPdelta and Sp1 at the GC-enriched promoter region synergizes the IL-10 gene transcription in mouse macrophage. J Biomed Sci. 2006; 13(5):621-35.
8. Bhavsar P, Ahmad T and Adcock IM. The role of histone deacetylases in asthma and allergic diseases. J Allergy Clin Immunol. 2008 ; 121(3): 580-4.
9. Adcock IM, Tsaprouni L, Bhavsar P, et al. Epigenetic regulation of airway inflammation. Curr Opin Immunol. 2007; 19(6):694-700.
10. Ito K, Charron CE and Adcock IM. Impact of protein acetylation in inflammatory lung diseases. Pharmacol Ther. 2007; 116(2):249-65.
11.Bilodeau S, Vallette-Kasic S, Gauthier Y, et al. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006; 20(20):2871-86.
12. Necela BM, Cidlowski JA. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. The American Thoracic society.2004; l(3):239-46.
13. Maneechotesuwan K, X Yao, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. J Immunol 2007; 178(4):2491-98.
14. Ogata k, Sato K and Tahirov. Eukarykotic transcriptional regulatory complexes: cooperativity from near and afar. Curropin in Stru Biol.2003; 13(1):40-8.
1.Fireman P.Understanding asthma pathophysiology.Allergy Asthma Proc.2003;24(2):79-83
2.Haller JS.Therapeutic mule:the use of arsenic in the nineteeth century material medica.Parmacy in History,1975;17(3):87-100.
3.殷凯生,姚欣,陈俊娣等.在实验动物中砷剂平喘机制的研究[J]南京医科大学学报,1999,19(5):433-4.
4.丁礼仁,沈华浩,崔巍.砷剂对支气管哮喘大鼠气道炎症的影响.中华结核和呼吸杂志;2002,25(11):686-7.
5.Ngoc PL,Gold DR,Tzianabos AO,et al.Cytokines,allergy,and asthma.Curr Opin Allergy Clin Immunol.2005;5(2):161-6.
6.Wills-Karp M,Luyimbazi J,Xu X,et al.Interleukin-13:central mediator of allergic asthma.Science.1998;(282):2258-61.
7.Wilson MS,Elnekave E,Mentink-Kane MM,et al.IL-13Ralpha2and IL-10 coordinately suppress airway inflammation,air way-hyperreactivity,and fibrosis in mice.J Clin Invest.2007;117(10):2941-51
8.Mackenzie AN,Li X,Largaespada DA,et al.structural comparion and chromosomal Localization of the human and the mouse IL-13gene.J Immunal 1993,150(12):5436-44
9.Blanchard C,Mishra A,Saito H,et al.Inhibition of human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-interleukin-13 antibody.Clin Exp Allergy.2005,35(8):1104-11.
10.Hirst SJ,Hallsworth MP,Peng QI,et al.Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1B and is mediated by the interleukin-4 receptor αchain.Am J Respir Crit Care Med,2002,165(8):1161-71.
11.Laoukili J,Perret E,Willems T,et al.IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells.Clin Invest,2001,108(12):1817-24.
12.Yamashita N,Tashimo H,Ishida Y,et al.Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness.Am J Physiol Lung Cell Mol Physiol.2006,290(6):1045-51.
13. Laporte JC, Moore PE, Baraldo S, et al. Direct effects of inter-leukin-13 on signaling pathways for physiologic responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med, 2001, 164(1): 141-8.
14. Booth BW, Sandifer T, Martin LD , et al.IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17. Respir Res,2007,8(1) :48-51.
15. Maneechotesuwan K, Xin Y, Ito K, et al. Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3. Immunol 2007, 178(4):2491-8.
16. Macian F. NFAT proteins: key regulators of T-cell development and Function. Nat Rev Immunol. 2005; 5(6):472-84.
17. Xin Y, Lee KY, Jazrawi EP, et al. The expression of interleukin-13 gene is regulated by NFAT1 in Hut-78 cells. Eur Respir J. 2005,26(8):232-4.
1.Mackenzie AN,Li X,Largaespada DA,et al.structural comparion and chromosomal localization of the human and the mouse IL-13genes J Immunal,1993,150(12):5436-44.
2. Songyang, Z., S. E. Shoelson, M. Chaudhuri, et al . SH2 domains recognize specific phosphopeptide sequences. Cell 1993 (72):767.
3. Fichtner-Feigl S, Strober W, Kawakami K,et al.Interleukin-13 signaling through the IL-13α2receptor is involved in induction of TGF-β1 production and fibrosis. Nat Med. 2006 Jan;12(1):99-106.
4. Kishikawa H, Sunday J, Choi A, et al. The cell type-specific expression of the murine IL-13 gene is regulated by GATA-3. [J] J Immunol. 2002;(167):4414-20.
5. Faith A, Richards DF, Verhoef A, et al. Impaired secretion ofmter-leukin-4 and interleukin-13 by allergen-specific T cells correlates with defective nuclear expression of NF-AT2 and jun B: relevance to immunotherapy. [J] Clin Exp Allergy. 2003;(33):1209-15
6. Wills-Karp M, Luyimbazi J, Xu X, etal.Interleukin-13:central mediator of allergic asthma. Science. 1998;(282):2258-61.
7. Venkayya R, Lam M, Willkom M, et al. The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsive-ness through direct effects on resident airway cells. Am J Respir Cell Mol Biol. 2002(26):202-08.
8. Grunstein MM, Hakonarson H, Leiter J, et al. IL-13-dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2002(282):L520-28.
9. Li L, Xia Y, Nguyen A, et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelialcells. J Immunol. 1999(162):2477-87.
10. Zimmerman N, Hershey GK, Foster PS, Rothenberg ME. Chemokines in asthma, cooperative interaction between chemoki-nes and IL-13. J Allergy Clin Immunol 2003(111):227-242.
11. Aliman MZ , Piazza FM , selby DM , et al . Muc25/5al mucin-messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. Am J Respir Cell Mol Biol ,2002 ,(22): 253-260.
12. Danahay H, Atherton H, Jones G, Bridges RJ, Poll CT. Inter-leukin-13 induces a hypersecretory ion transport phenotype in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2002 (282) :L226 -L236.
13. Pope SM, Brandt EB, Mishra A, et al. IL-13 induces eosinophil recruitment into the lung by an IL-5 and eotaxin-dependent mechanism. J Allergy Clin Immunol. 2001; 108:594-601.
14. Zimmermann N, et al. Dissection ofexperimental asthma with DNA microarray analysis identifies arginase in asthma pathogene-sis. J Clin Invest 2003(111): 1863 -1874.
15. Richter A, Puddicombe SM, Lordan JL, et al. The contribution of interleukin (IL) -4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma. Am J Respir CellMolBio2001(25):385-91.
16. Wen FQ, Kohyama T, Liu X, et al. Interleukin-4- and interleukin-13-enhanced transforming growth factor beta-2 production in cultured human bronchial epithelial cells is attenuated by inter-feron-gamma. Am J Respir Cell Mol Biol. 2002(26):484-90.
17. Esp inosa K,Bosse Y, Stankova J, et al. CysLTl recep tor up regulationby TGF-beta and IL-13 is associated with bronchial smooth muscle cell p roliferation in response to LTD4 [J]. J A llergy Clin Imm unol,2003, 111 (5): 1032-1040
18.Kumar RK,Herbert C,Foster PS.Expression of growth factors by air-way ep ithelial cells in a model of chronic asthma:regulation and relationship to subep ithelial fibrosis[J].Clin Exp A llergy,2004,34(4):567-575.