Cargando…

Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes

BACKGROUND: Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Matrix metalloproteinases (MMPs) ar...

Descripción completa

Detalles Bibliográficos
Autores principales: Korotkov, Anatoly, Broekaart, Diede W. M., van Scheppingen, Jackelien, Anink, Jasper J., Baayen, Johannes C., Idema, Sander, Gorter, Jan A., Aronica, Eleonora, van Vliet, Erwin A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054845/
https://www.ncbi.nlm.nih.gov/pubmed/30031401
http://dx.doi.org/10.1186/s12974-018-1245-y
_version_ 1783341070277410816
author Korotkov, Anatoly
Broekaart, Diede W. M.
van Scheppingen, Jackelien
Anink, Jasper J.
Baayen, Johannes C.
Idema, Sander
Gorter, Jan A.
Aronica, Eleonora
van Vliet, Erwin A.
author_facet Korotkov, Anatoly
Broekaart, Diede W. M.
van Scheppingen, Jackelien
Anink, Jasper J.
Baayen, Johannes C.
Idema, Sander
Gorter, Jan A.
Aronica, Eleonora
van Vliet, Erwin A.
author_sort Korotkov, Anatoly
collection PubMed
description BACKGROUND: Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Matrix metalloproteinases (MMPs) are proteolytic enzymes largely responsible for the remodeling of the ECM. The inhibition of MMPs has been suggested as a novel therapy for epilepsy; however, available MMP inhibitors lack specificity and cause serious side effects. We studied whether MMPs could be modulated via microRNAs (miRNAs). Several miRNAs mediate inflammatory responses in the brain, which are known to control MMP expression. The aim of this study was to investigate whether an increased expression of MMPs after interleukin-1β (IL-1β) stimulation can be attenuated by inhibition of the inflammation-associated miR-155. METHODS: We investigated the expression of MMP2, MMP3, MMP9, and MMP14 in cultured human fetal astrocytes after stimulation with the pro-inflammatory cytokine IL-1β. The cells were transfected with miR-155 antagomiR, and the effect on MMP3 expression was investigated using real-time quantitative PCR and Western blotting. Furthermore, we characterized MMP3 and miR-155 expression in brain tissue of TLE patients with hippocampal sclerosis (TLE-HS) and during epileptogenesis in a rat TLE model. RESULTS: Inhibition of miR-155 by the antagomiR attenuated MMP3 overexpression after IL-1β stimulation in astrocytes. Increased expression of MMP3 and miR-155 was also evident in the hippocampus of TLE-HS patients and throughout epileptogenesis in the rat TLE model. CONCLUSIONS: Our experiments showed that MMP3 is dynamically regulated by seizures as shown by increased expression in TLE tissue and during different phases of epileptogenesis in the rat TLE model. MMP3 can be induced by the pro-inflammatory cytokine IL-1β and is regulated by miR-155, suggesting a possible strategy to prevent epilepsy via reduction of inflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1245-y) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6054845
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-60548452018-07-23 Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes Korotkov, Anatoly Broekaart, Diede W. M. van Scheppingen, Jackelien Anink, Jasper J. Baayen, Johannes C. Idema, Sander Gorter, Jan A. Aronica, Eleonora van Vliet, Erwin A. J Neuroinflammation Research BACKGROUND: Temporal lobe epilepsy (TLE) is a chronic neurological disease, in which about 30% of patients cannot be treated adequately with anti-epileptic drugs. Brain inflammation and remodeling of the extracellular matrix (ECM) seem to play a major role in TLE. Matrix metalloproteinases (MMPs) are proteolytic enzymes largely responsible for the remodeling of the ECM. The inhibition of MMPs has been suggested as a novel therapy for epilepsy; however, available MMP inhibitors lack specificity and cause serious side effects. We studied whether MMPs could be modulated via microRNAs (miRNAs). Several miRNAs mediate inflammatory responses in the brain, which are known to control MMP expression. The aim of this study was to investigate whether an increased expression of MMPs after interleukin-1β (IL-1β) stimulation can be attenuated by inhibition of the inflammation-associated miR-155. METHODS: We investigated the expression of MMP2, MMP3, MMP9, and MMP14 in cultured human fetal astrocytes after stimulation with the pro-inflammatory cytokine IL-1β. The cells were transfected with miR-155 antagomiR, and the effect on MMP3 expression was investigated using real-time quantitative PCR and Western blotting. Furthermore, we characterized MMP3 and miR-155 expression in brain tissue of TLE patients with hippocampal sclerosis (TLE-HS) and during epileptogenesis in a rat TLE model. RESULTS: Inhibition of miR-155 by the antagomiR attenuated MMP3 overexpression after IL-1β stimulation in astrocytes. Increased expression of MMP3 and miR-155 was also evident in the hippocampus of TLE-HS patients and throughout epileptogenesis in the rat TLE model. CONCLUSIONS: Our experiments showed that MMP3 is dynamically regulated by seizures as shown by increased expression in TLE tissue and during different phases of epileptogenesis in the rat TLE model. MMP3 can be induced by the pro-inflammatory cytokine IL-1β and is regulated by miR-155, suggesting a possible strategy to prevent epilepsy via reduction of inflammation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12974-018-1245-y) contains supplementary material, which is available to authorized users. BioMed Central 2018-07-21 /pmc/articles/PMC6054845/ /pubmed/30031401 http://dx.doi.org/10.1186/s12974-018-1245-y Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Korotkov, Anatoly
Broekaart, Diede W. M.
van Scheppingen, Jackelien
Anink, Jasper J.
Baayen, Johannes C.
Idema, Sander
Gorter, Jan A.
Aronica, Eleonora
van Vliet, Erwin A.
Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
title Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
title_full Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
title_fullStr Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
title_full_unstemmed Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
title_short Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes
title_sort increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microrna-155 in cultured human astrocytes
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054845/
https://www.ncbi.nlm.nih.gov/pubmed/30031401
http://dx.doi.org/10.1186/s12974-018-1245-y
work_keys_str_mv AT korotkovanatoly increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT broekaartdiedewm increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT vanscheppingenjackelien increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT aninkjasperj increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT baayenjohannesc increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT idemasander increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT gorterjana increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT aronicaeleonora increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes
AT vanvlieterwina increasedexpressionofmatrixmetalloproteinase3canbeattenuatedbyinhibitionofmicrorna155inculturedhumanastrocytes