Journal article

Publication year: 2021

Pages: 140-148

Journal: Journal of Cystic Fibrosis

Volume number: 20

Issue number: 1

ISSN: 1569-1993

eISSN: 1873-5010

Open access status: Hybrid

DOI Link: https://doi.org/10.1016/j.jcf.2020.05.006

Publisher: Elsevier

Abstract: 

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.

Harvard Citation style: Chillappagari, S., Garapati, V., Mahavadi, P., Naehrlich, L., Schmeck, B., Schmitz, M., et al. (2021) Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells, Journal of Cystic Fibrosis, 20(1), pp. 140-148. https://doi.org/10.1016/j.jcf.2020.05.006

APA Citation style: Chillappagari, S., Garapati, V., Mahavadi, P., Naehrlich, L., Schmeck, B., Schmitz, M., & Guenther, A. (2021). Defective BACH1/HO-1 regulatory circuits in cystic fibrosis bronchial epithelial cells. Journal of Cystic Fibrosis. 20(1), 140-148. https://doi.org/10.1016/j.jcf.2020.05.006