Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation.
Foxa2 regulates leukotrienes to inhibit Th2-mediated pulmonary inflammation.
复制标题
DOI：
10.1165/rcmb.2013-0122oc
复制
发表时间：
2013-12
影响因子：
6.4
通讯作者：
Xiaoju Tang;Xiaojing Liu;Cuijie Tian;Qiao-li Su;Y. Lei;Qingbo Wu;Yangyan He;J. Whitsett;F. Luo
中科院分区：
文献类型：
--
作者：
Xiaoju Tang;Xiaojing Liu;Cuijie Tian;Qiao-li Su;Y. Lei;Qingbo Wu;Yangyan He;J. Whitsett;F. Luo
FOXA2是核转录因子Forkhead家族的成员之一，在发育和成熟的肺的呼吸道上皮细胞中高表达。FOXA2是正常的呼吸道上皮细胞分化所必需的，它的缺失会在出生后发育过程中导致杯状细胞化生和Th2介导的肺部炎症。FOXA2的表达在空气变应原致敏和Th2细胞因子刺激后受到抑制，当其丢失与杯状细胞化生有关时。Foxa2调控呼吸道上皮细胞分化和Th2免疫的机制尚不完全清楚。在出生后的头两周，Foxa2基因的缺失会增加Foxa2基因靶向小鼠肺内白三烯(LTs)和Th2细胞因子的产生。FOXA2的表达抑制了15-脂氧合酶(ALOX15)，并增加了ALOX5的转录，每一个都编码与哮喘相关的关键脂氧合酶。孟鲁司特抑制半胱氨酸基转移酶(CysLT)信号通路，抑制IL-4、IL-5、eoaxin-2，并调节Foxa2基因靶向发育小鼠肺内正常T细胞的表达和分泌表达。孟鲁司特抑制黏液化生调控基因的表达，包括SPDEF、Muc5ac、Foxa3和Arg2。FOXA2在呼吸道上皮细胞中发挥细胞自主作用，是抑制Th2免疫和发育中肺粘液化生所必需的，这一过程部分由其对CysLT途径的调节决定。
Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene-targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene-targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway.