STAT1 activation causes translocation of Bax to the endoplasmic reticulum during the resolution of airway mucous cell hyperplasia by IFN-γ
STAT1 activation causes translocation of Bax to the endoplasmic reticulum during the resolution of airway mucous cell hyperplasia by IFN-γ
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DOI：
10.4049/jimmunol.178.12.8107
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发表时间：
2007-06-15
影响因子：
4.4
通讯作者：
Tesfaigzi, Yohannes
中科院分区：
文献类型：
--
作者：
Stout, Barbara A.;Melendez, Karla;Tesfaigzi, Yohannes
炎症诱导的粘液细胞增生的正常分解过程的破坏可导致慢性疾病中持续的粘液14分泌过多。在小鼠长时间暴露于过敏原期间，IFN-γ减少粘液细胞增生，但导致细胞死亡的信号传导在很大程度上是未知的。在气道上皮细胞（AEC）中，细胞死亡需要IFN-γ对STAT 1的短暂磷酸化，并且在长期暴露于过敏原期间，STAT 1（-/-）小鼠中的粘液细胞增生保持升高，但在STAT 1（-/-）小鼠中消退。虽然IFN-γ治疗的原代人AEC和其他气道细胞系的Bax蛋白水平不变，它引起的Bax从胞质易位到内质网（ER），但不是线粒体。在从STAT 1（+/+）小鼠分离的经IFN-γ处理的原代AEC中观察到Bax定位于ER，但在从STAT 1（-/-）小鼠分离的细胞中未观察到Bax定位于ER。此外，ER Bax在长时间暴露于过敏原的小鼠的STAT 1（+/+）而不是STAT 1（-/-）气道的粘液细胞中被检测到。IFN-γ不会从线粒体释放细胞色素c，但会减少ER钙储存并扩张ER，证实IFN-γ诱导的细胞死亡是通过ER局部的变化介导的。总的来说，这些观察结果表明，STAT 1依赖的Bax易位到ER是至关重要的IFN-γ诱导的AEC细胞死亡和过敏原诱导的粘液细胞增生的决议。
Disruption of the normal resolution process of inflammation-induced mucous cell hyperplasia may lead to sustained mucous 14 hypersecretion in chronic diseases. During prolonged exposure of mice to allergen, IFN-gamma reduces mucous cell hyperplasia, but the signaling responsible for the cell death is largely unknown. A brief phosphorylation of STAT1 by IFN-gamma was required for cell death in airway epithelial cells (AEC), and during prolonged exposure to allergen, mucous cell hyperplasia remained elevated in STAT1(-/-) but was resolved in STAT1(-/-) mice. Although IFN-gamma treatment of primary human AECs and other airway cell lines left Bax protein levels unchanged, it caused translocation of Bax from the cytosol to the endoplasmic reticulum (ER) but not to the mitochondria. Localization of Bax to the ER was observed in IFN-gamma-treated primary AECs isolated from STAT1(+/+) mice but not in cells from STAT1(-/-) mice. In addition, ER Bax was detected in mucous cells of STAT1(+/+) but not STAT1(-/-) airways of mice exposed to allergen for prolonged periods. IFN-gamma did not release cytochrome c from mitochondria but reduced ER calcium stores and dilated the ER, confirming that the IFN-gamma-induced cell death is mediated through changes localized in the ER. Collectively, these observations suggest that STAT1-dependent translocation of Bax to the ER is crucial for IFN-gamma-induced cell death of AECs and the resolution of allergen-induced mucous cell hyperplasia.