NDLI: Exogenous neutrophil elastase enters bronchial epithelial cells and suppresses cigarette smoke extract–induced heme oxygenase-1 by cleaving sirtuin 1

Content Provider	Journal of Biological Chemistry (JBC)
Author	Lee, Kyoung-Hee Jeong, Jiyeong Koo, Yoon-Jung Jang, An-Hee Lee, Chang-Hoon Yoo, Chul-Gyu
Abstract	An imbalance between oxidative stress and antioxidant activity plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke, a major risk factor of COPD, induces cellular oxidative stress, but levels of antioxidants such as heme oxygenase-1 (HO-1) are reduced in individuals with severe COPD. In this study, we evaluated the molecular mechanism of reduced HO-1 expression in human bronchial epithelial cells. We found that cigarette smoke extract (CSE) increases HO-1 levels via activation of NFE2-related factor 2 (Nrf2). However, pretreating cells with the protease neutrophil elastase (NE) suppressed the CSE-induced expression of HO-1 mRNA and protein. NE also decreased the sirtuin 1 (SIRT1) level, but did not inhibit CSE-induced nuclear translocation and DNA-binding activity of Nrf2. Transfection of cells with a Myc/His-tagged SIRT1 expression vector completely blocked the NE-mediated suppression of HO-1 expression. We further noted that the NE-induced down-regulation of SIRT1 was not due to decreased transcription or proteasomal/lysosomal degradation or loss of solubility. Immunofluorescence staining revealed that NE enters the cell cytoplasm, and we observed that NE directly cleaved SIRT1 in vitro, indicating that SIRT1 levels are decreased via direct degradation by internalized NE. Of note, we observed decreased SIRT1 levels in NE-treated primary human bronchial epithelial cells and in lung homogenates from both smokers and patients with COPD. In conclusion, NE suppresses CSE-induced HO-1 expression by cleaving SIRT1. This finding indicates the importance of cross-talk between oxidative stress and protease responses in the pathogenesis of COPD.
Related Links	http://www.jbc.org/content/292/28/11970.abstract
Ending Page	11979
Starting Page	11970
Page Count	10
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	28
Volume Number	292
DOI	10.1074/jbc.M116.771089
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2017-07-14
Access Restriction	Open
Subject Keyword	Antioxidant Chronic obstructive pulmonary disease (COPD) Oxidative stress Pathogenesis Sirtuin 1 (SIRT1) Cigarette smoke extract Heme oxygenase 1 Neutrophil elastase Molecular Bases of Disease
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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