Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis.
Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis.
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DOI：
10.1164/rccm.200612-1887oc
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发表时间：
2007-11
影响因子：
24.7
通讯作者：
Y. Matsuno;Yukio Ishii;K. Yoh;Y. Morishima;N. Haraguchi;N. Kikuchi;T. Iizuka;T. Kiwamoto;S. Homma;A. Nomura;T. Sakamoto;M. Ohtsuka;N. Hizawa;Satoru Takahashi
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文献类型：
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作者：
Y. Matsuno;Yukio Ishii;K. Yoh;Y. Morishima;N. Haraguchi;N. Kikuchi;T. Iizuka;T. Kiwamoto;S. Homma;A. Nomura;T. Sakamoto;M. Ohtsuka;N. Hizawa;Satoru Takahashi
原理：过敏性肺炎（HP）是由Th1免疫应答介导的。转录因子GATA结合蛋白-3 （GATA-3）被认为是Th2分化的关键调节因子，因此可能在过敏性肺炎（HP）的发病机制中发挥调节作用。目的研究GATA-3过表达对小鼠HP发病的影响。方法以C57BL/6野生型小鼠和gata -3过表达小鼠为研究对象。通过反复暴露于农民肺的致病抗原直状糖多孢子菌诱导HP。在野生型小鼠中，抗原暴露导致明显的炎症反应，肺中T-bet和Th1细胞因子干扰素(IFN)- γ的表达增强。gata -3过表达小鼠的肺部炎症程度较轻。抗原暴露后，过表达gata -3的小鼠肺中T-bet和ifn - γ基因的诱导被抑制，但Th2细胞因子，包括IL-5和IL-13，被显著诱导。在gata -3过表达小鼠中，补充重组ifn - γ可将肺部炎症反应增强至野生型小鼠的水平。由于抗原诱导的ifn - γ产生主要发生在CD4+ T细胞中，因此将裸鼠与野生型或过表达gata -3的小鼠的CD4+ T细胞一起转移，随后暴露于抗原。转染gata -3过表达小鼠的CD4+ T细胞的裸鼠肺部炎症反应明显低于转染野生型CD4+ T细胞的裸鼠，肺部ifn - γ水平降低。结论GATA-3的过表达可通过纠正th1极化条件来减缓HP的发展。
RATIONALE Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP). OBJECTIVES We examined the effect of GATA-3 overexpression on the development of HP in mice. METHODS Wild-type C57BL/6 mice and GATA-3-overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmer's lung. MEASUREMENTS AND MAIN RESULTS Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN)-gamma in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3-overexpressing mice. The induction of T-bet and IFN-gamma genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3-overexpressing mice after antigen exposure. Supplementation with recombinant IFN-gamma enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-gamma production predominantly occurred in CD4+ T cells, nude mice were transferred with CD4+ T cells from either wild-type or GATA-3-overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4+ T cells from GATA-3-overexpressing mice than in those with wild-type CD4+ T cells, with a reduction of lung IFN-gamma level. CONCLUSIONS These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.