Matsuzaki Yohei, Besnard Valérie, Clark Jean C, Xu Yan, Wert Susan E, Ikegami Machiko, Whitsett Jeffrey A
Cincinnati Children's Hospital Medical Center, Section of Neonatology, Perinatal and Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Am J Respir Cell Mol Biol. 2008 May;38(5):551-8. doi: 10.1165/rcmb.2007-0311OC. Epub 2007 Dec 20.
ATP-Binding Cassette A3 (ABCA3) is a lamellar body associated lipid transport protein required for normal synthesis and storage of pulmonary surfactant in type II cells in the alveoli. In this study, we demonstrate that STAT3, activated by IL-6, regulates ABCA3 expression in vivo and in vitro. ABCA3 mRNA and immunostaining were decreased in adult mouse lungs in which STAT3 was deleted from the respiratory epithelium (Stat3(Delta/Delta) mice). Consistent with the role of STAT3, intratracheal IL-6 induced ABCA3 expression in vivo. Decreased ABCA3 and abnormalities in the formation of lamellar bodies, the intracellular site of surfactant lipid storage, were observed in Stat3(Delta/Delta) mice. Expression of SREBP1a and 1c, SCAP, ABCA3, and AKT mRNAs was inhibited by deletion of Stat3 in type II cells isolated from Stat3(Delta/Delta) mice. The activities of PI3K and AKT were required for normal Abca3 gene expression in vitro. AKT activation induced SREBP expression and increased the activity of the Abca3 promoter in vitro, consistent with the role of STAT3 signaling, at least in part via SREBP, in the regulation of ABCA3. ABCA3 expression is regulated by IL-6 in a pathway that includes STAT3, PI3K, AKT, SCAP, and SREBP. Activation of STAT3 after exposure to IL-6 enhances ABCA3 expression, which, in turn, influences pulmonary surfactant homeostasis.
ATP结合盒转运体A3（ABCA3）是一种与板层小体相关的脂质转运蛋白，是肺泡II型细胞中肺表面活性物质正常合成和储存所必需的。在本研究中，我们证明，由白细胞介素-6激活的信号转导和转录激活因子3（STAT3）在体内和体外调节ABCA3的表达。在呼吸上皮细胞中STAT3被敲除的成年小鼠肺中（Stat3(Delta/Delta)小鼠），ABCA3信使核糖核酸（mRNA）和免疫染色减少。与STAT3的作用一致，气管内注射白细胞介素-6在体内诱导ABCA3表达。在Stat3(Delta/Delta)小鼠中观察到ABCA3减少以及板层小体形成异常，板层小体是表面活性物质脂质储存的细胞内场所。从Stat3(Delta/Delta)小鼠分离的II型细胞中，Stat3的缺失抑制了固醇调节元件结合蛋白1a和1c（SREBP1a和1c）、SCAP、ABCA3和AKT mRNA的表达。体外PI3K和AKT的活性是正常Abca3基因表达所必需的。AKT激活在体外诱导SREBP表达并增加Abca3启动子的活性，这与STAT3信号传导的作用一致，至少部分是通过SREBP调节ABCA3。ABCA3的表达在一条包括STAT3、PI3K、AKT、SCAP和SREBP的信号通路中受白细胞介素-6调节。暴露于白细胞介素-6后STAT3的激活增强了ABCA3的表达，进而影响肺表面活性物质的稳态。
