Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells
Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells
复制标题
囊性纤维化支气管上皮细胞BACH1/HO-1调控通路缺陷
DOI：
10.1016/j.jcf.2020.05.006
复制
发表时间：
2021-01-29
影响因子：
5.2
通讯作者：
Guenther, Andreas
中科院分区：
文献类型：
--
作者：
Chillappagari, Shashipavan;Garapati, Virajith;Guenther, Andreas
Background: The stress-regulated enzyme hemeoxygenase-1 (HO-1) contributes to the cell response towards inflammation and oxidative stress. We previously reported on curtailed HO-1 expression in cystic fibrosis (CF) bronchial epithelial (CFBE41o-) cells and CF-mice, but the molecular mechanisms for this are not known. Here, we compared healthy and CF bronchial epithelial cells for regulatory circuits controlling HO-1 protein levels.Methods: In this study, we employed immunohistochemistry on CF and healthy lung sections to examine the BACH1 protein expression. Alteration of BACH1 protein levels in 16HBE14o- and CFBE41o- cells was achieved by using either siRNA-mediated knockdown of BACH1 or by increasing miRNA-155 levels. HO-1 luciferase reporter assay was chosen to examine the downstream affects after BACH1 modulation.Results: Human CF lungs and cells showed increased levels of the HO-1 transcriptional repressor, BACH1, and increased miR-155 expression. Knockdown studies using BACH1 siRNA and overexpression of miR-155 did not significantly rescue HO-1 expression in CFBE41o- cells. Elevated BACH1 expression detected in CF cells was refractory to the inhibitory function of miR-155 and was instead due to increased protein stability.Conclusion: We observed defects in the inhibitory activities of miR-155 and BACH1 on HO-1 expression in CF cells. Thus various defective regulatory loops account for dysregulated BACH1 expression in CF, which in turn may contribute to low HO-1 levels. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.
