Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness
Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness
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DOI：
10.1152/ajplung.00195.2005
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发表时间：
2006-06-01
影响因子：
4.9
通讯作者：
Ohta, K
中科院分区：
文献类型：
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作者：
Yamashita, N;Tashimo, H;Ohta, K
支气管哮喘的病理生理特征包括气道慢性炎症、气道高反应性和支气管收缩。研究表明，气道中T细胞和肥大细胞产生的辅助性T型2 （Th2）细胞因子在实验和人支气管哮喘的炎症启动中起重要作用。GATA-3是T淋巴细胞产生Th2细胞因子所必需的转录因子。为了阐明表达GATA-3的T细胞在支气管哮喘病理生理中的作用，我们利用携带GATA-3基因和卵清蛋白（OVA）特异性T细胞受体基因（GATA-3-Tg/OVA-Tg）的转基因（Tg）小鼠。小鼠经鼻给药OVA，不进行全身免疫。采用无创和有创全身体积脉搏仪分析气道反应。GATA-3-Tg/OVA-Tg小鼠气道内IL-13和IL-4蛋白表达显著升高。虽然GATA-3-Tg/OVA- tg与GATA-3-non-Tg/OVA- tg小鼠的浸润细胞类型没有差异，两组小鼠的IgE水平与未处理小鼠相比均无显著升高，但在经OVA鼻内治疗的第7天，GATA-3-Tg/OVA- tg吸入ACh后的反应显著升高。这种高反应性被5-脂氧合酶抑制剂和IL-13中和抑制，表明气道反应是通过IL-13和白三烯途径诱导的。综上所述，气道高反应性是支气管哮喘的一个特征，在体内受T淋巴细胞在GATA-3转录水平上的调节。
The pathophysiological characteristics of bronchial asthma consist of chronic inflammation of airways, airway hyperresponsiveness, and bronchoconstriction. Studies have shown that T helper type 2 (Th2) cytokines produced by both T cells and mast cells in the airway contribute substantially to the initiation of inflammation in both experimental and human bronchial asthma. GATA-3 is a transcription factor essential to the production of Th2 cytokines by T lymphocytes. To clarify the role of GATA-3-expressing T cells in the pathophysiology of bronchial asthma, we utilized transgenic (Tg) mice carrying the GATA-3 gene and the ovalbumin (OVA)-specific T cell receptor gene (GATA-3-Tg/OVA-Tg). Mice were intranasally administrated OVA without systemic immunization. Airway responses were analyzed with noninvasive and invasive whole body plethysmographs. GATA-3-Tg/OVA-Tg mice exhibited significantly higher IL-13 and IL-4 protein expression in the airway. Although there were no differences in the types of infiltrating cells between GATA-3-Tg/OVA-Tg and GATA-3-non-Tg/OVA-Tg mice and no significant increase in IgE level in either group compared with nontreated mice, the response after ACh inhalation was significantly elevated in GATA-3-Tg/OVA-Tg on the seventh day of intranasal treatment with OVA. This hyperresponsiveness was inhibited by 5-lipoxygenase inhibitor and IL-13 neutralization, suggesting that airway responses were induced through IL-13 and leukotriene pathway. In conclusion, airway hyperresponsiveness, a characteristic of bronchial asthma, is regulated at the level of GATA-3 transcription by T lymphocytes in vivo.