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Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells
BACKGROUND: Inflammation, angiogenesis and oxidative stress have been implicated in the pathogenesis of various vascular diseases. Recent evidence suggests that dimethylfumarate (DMF), an antiposriatic and anti-multiple sclerosis agent, possesses anti-inflammatory, anti-oxidative and anti-angiogenic...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525722/ https://www.ncbi.nlm.nih.gov/pubmed/26246800 http://dx.doi.org/10.1186/s12950-015-0094-z |
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author | Gerhardt, Simon König, Veronika Doll, Monika Hailemariam-Jahn, Tsige Hrgovic, Igor Zöller, Nadja Kaufmann, Roland Kippenberger, Stefan Meissner, Markus |
author_facet | Gerhardt, Simon König, Veronika Doll, Monika Hailemariam-Jahn, Tsige Hrgovic, Igor Zöller, Nadja Kaufmann, Roland Kippenberger, Stefan Meissner, Markus |
author_sort | Gerhardt, Simon |
collection | PubMed |
description | BACKGROUND: Inflammation, angiogenesis and oxidative stress have been implicated in the pathogenesis of various vascular diseases. Recent evidence suggests that dimethylfumarate (DMF), an antiposriatic and anti-multiple sclerosis agent, possesses anti-inflammatory, anti-oxidative and anti-angiogenic properties. Here, we analyze the influence of DMF on TNF-α-induced expression of the important pro-inflammatory and pro-atherogenic chemokine MCP-1 and investigate the underlying mechanisms of this expression. FINDINGS: We analyzed constitutive and TNF-α-induced expression of MCP-1 in human umbilical vascular endothelial cells (HUVEC) +/− DMF treatment via enzyme-linkes immunosorbent assay (ELISA). DMF significantly inhibited the protein expression levels in a time- and concentration-dependent manner. Furthermore, MCP-1 mRNA expression was also reduced in response to DMF, as demonstrated by RT-PCR. Thus, the regulation occurs at the transcriptional level. Interestingly, DMF prolonged the TNF-α-induced p38 and JNK phosphorylation in HUVEC, as demonstrated by Western blot analysis; however, the p38 and JNK inhibitor SB203580 did not affect the DMF-conveyed suppression of TNF-α-induced MCP-1 expression. DMF suppressed the TNF-α-induced nuclear translocation and phosphorylation (Serine 536) of p65 in these cells. These results were additionally approved by p65 luciferase promoter assays. Furthermore, we found that DMF slightly inhibited the early degradation of IκBα. In addition, we verified our results using other important inflammatory cytokines such as CCL-5, PDGF-BB, GM-CSF and IL-6. CONCLUSION: DMF suppresses various TNF-α-induced pro-inflammatory and pro-atherogenic cytokines/chemokines in human endothelial cells. This action is regulated by reduced p65 activity and nuclear translocation, which can be explained in part by the reduced early degradation of IκBα and more important the reduced phosphorylation of p65 at Serine 536. These effects were independent of the p38, PI3K and p42/44 signaling pathways. As a result, DMF might be suitable for treating patients with vascular diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12950-015-0094-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4525722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-45257222015-08-06 Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells Gerhardt, Simon König, Veronika Doll, Monika Hailemariam-Jahn, Tsige Hrgovic, Igor Zöller, Nadja Kaufmann, Roland Kippenberger, Stefan Meissner, Markus J Inflamm (Lond) Short Report BACKGROUND: Inflammation, angiogenesis and oxidative stress have been implicated in the pathogenesis of various vascular diseases. Recent evidence suggests that dimethylfumarate (DMF), an antiposriatic and anti-multiple sclerosis agent, possesses anti-inflammatory, anti-oxidative and anti-angiogenic properties. Here, we analyze the influence of DMF on TNF-α-induced expression of the important pro-inflammatory and pro-atherogenic chemokine MCP-1 and investigate the underlying mechanisms of this expression. FINDINGS: We analyzed constitutive and TNF-α-induced expression of MCP-1 in human umbilical vascular endothelial cells (HUVEC) +/− DMF treatment via enzyme-linkes immunosorbent assay (ELISA). DMF significantly inhibited the protein expression levels in a time- and concentration-dependent manner. Furthermore, MCP-1 mRNA expression was also reduced in response to DMF, as demonstrated by RT-PCR. Thus, the regulation occurs at the transcriptional level. Interestingly, DMF prolonged the TNF-α-induced p38 and JNK phosphorylation in HUVEC, as demonstrated by Western blot analysis; however, the p38 and JNK inhibitor SB203580 did not affect the DMF-conveyed suppression of TNF-α-induced MCP-1 expression. DMF suppressed the TNF-α-induced nuclear translocation and phosphorylation (Serine 536) of p65 in these cells. These results were additionally approved by p65 luciferase promoter assays. Furthermore, we found that DMF slightly inhibited the early degradation of IκBα. In addition, we verified our results using other important inflammatory cytokines such as CCL-5, PDGF-BB, GM-CSF and IL-6. CONCLUSION: DMF suppresses various TNF-α-induced pro-inflammatory and pro-atherogenic cytokines/chemokines in human endothelial cells. This action is regulated by reduced p65 activity and nuclear translocation, which can be explained in part by the reduced early degradation of IκBα and more important the reduced phosphorylation of p65 at Serine 536. These effects were independent of the p38, PI3K and p42/44 signaling pathways. As a result, DMF might be suitable for treating patients with vascular diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12950-015-0094-z) contains supplementary material, which is available to authorized users. BioMed Central 2015-08-06 /pmc/articles/PMC4525722/ /pubmed/26246800 http://dx.doi.org/10.1186/s12950-015-0094-z Text en © Gerhardt et al. 2015 Open Access This 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 | Short Report Gerhardt, Simon König, Veronika Doll, Monika Hailemariam-Jahn, Tsige Hrgovic, Igor Zöller, Nadja Kaufmann, Roland Kippenberger, Stefan Meissner, Markus Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells |
title | Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells |
title_full | Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells |
title_fullStr | Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells |
title_full_unstemmed | Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells |
title_short | Dimethylfumarate protects against TNF-α-induced secretion of inflammatory cytokines in human endothelial cells |
title_sort | dimethylfumarate protects against tnf-α-induced secretion of inflammatory cytokines in human endothelial cells |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525722/ https://www.ncbi.nlm.nih.gov/pubmed/26246800 http://dx.doi.org/10.1186/s12950-015-0094-z |
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