Ethanol increases matrix metalloproteinase-12 expression via NADPH oxidase-dependent ROS production in macrophages

Title
Ethanol increases matrix metalloproteinase-12 expression via NADPH oxidase-dependent ROS production in macrophages
Author(s)
박필훈김미진이응석정태천사로즈네팔김상현[김상현]
Keywords
ALCOHOLIC-LIVER-DISEASE; OXIDATIVE-STRESS; ALVEOLAR MACROPHAGES; POTENTIAL TREATMENT; GENE-EXPRESSION; CELLS; ACTIVATION; MMP-12; METALLOELASTASE; APOPTOSIS
Issue Date
201311
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.273, no.1, pp.77 - 89
Abstract
Matrix metalloproteinase-12 (MMP-12), an enzyme responsible for degradation of extracellular matrix, plays an important role in the progression of various diseases, including inflammation and fibrosis. Although most of those are pathogenic conditions induced by ethanol ingestion, the effect of ethanol on MMP-12 has not been explored. In the present study, we investigated the effect of ethanol on MMP-12 expression and its potential mechanisms in macrophages. Here, we demonstrated that ethanol treatment increased MMP-12 expression in primary murine peritoneal macrophages and RAW 264.7 macrophages at both mRNA and protein levels. Ethanol treatment also significantly increased the activity of nicotinamide adenine dinucleotide (NADPH) oxidase and the expression of NADPH oxidase-2 (Nox2). Pretreatment with an anti-oxidant (N-acetyl cysteine) or a selective inhibitor of NADPH oxidase (diphenyleneiodonium chloride (DPI)) prevented ethanol-induced MMP-12 expression. Furthermore, knockdown of Nox2 by small interfering RNA (siRNA) prevented ethanol-induced ROS production and MMP-12 expression in RAW 264.7 macrophages, indicating a critical role for Nox2 in ethanol-induced intracellular ROS production and MMP-12 expression in macrophages. We also showed that ethanol-induced Nox2 expression was suppressed by transient transfection with dominant negative IKB-alpha plasmid or pretreatment with Bay 11-7082, a selective inhibitor of NF-KB, in RAW 264.7 macrophages. In addition, ethanol-induced Nox2 expression was also attenuated by treatment with a selective inhibitor of p38 MAPK, suggesting involvement of p38 MAPK/NF-KB pathway in ethanolinduced Nox2 expression. Taken together, these results demonstrate that ethanol treatment elicited increase in MMP-12 expression via increase in ROS production derived from Nox2 in macrophages. (C) 2013 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/28568http://dx.doi.org/10.1016/j.taap.2013.08.005
ISSN
0041-008X
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약학대학 > 약학부 > Articles
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