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AICAR suppresses TNF-α-induced complement factor B in RPE cells
Age related macular degeneration is the leading cause of blindness in the developed world. Although its precise cause remains elusive, dysfunction of the retinal pigment epithelium (RPE) and dysregulation of complement have been implicated in its pathogenesis. The goal of this study was to evaluate...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732305/ https://www.ncbi.nlm.nih.gov/pubmed/29247196 http://dx.doi.org/10.1038/s41598-017-17744-w |
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author | Chung, Eun Jee Efstathiou, Nikolaos E. Konstantinou, Eleni K. Maidana, Daniel E. Miller, Joan W. Young, Lucy H. Vavvas, Demetrios G. |
author_facet | Chung, Eun Jee Efstathiou, Nikolaos E. Konstantinou, Eleni K. Maidana, Daniel E. Miller, Joan W. Young, Lucy H. Vavvas, Demetrios G. |
author_sort | Chung, Eun Jee |
collection | PubMed |
description | Age related macular degeneration is the leading cause of blindness in the developed world. Although its precise cause remains elusive, dysfunction of the retinal pigment epithelium (RPE) and dysregulation of complement have been implicated in its pathogenesis. The goal of this study was to evaluate the role of an AMP-dependent kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), on tumor necrosis factor alpha (TNF-α) induction of complement factor B (CFB) in RPE cells. We found that AICAR inhibited TNF-α-induced CFB expression in ARPE-19 and human primary RPE cells in a dose-dependent fashion. Treatment of cells with dipyridamole, which blocks AICAR cellular uptake abolished these effects. In contrast, the adenosine kinase inhibitor, 5-iodotubericidin, which inhibits the conversion of AICAR to the direct activator of AMPK, ZMP, did not reverse the effects on TNF-α-induced CFB expression, suggesting AMPK-independent effects. Indeed, knockout of AMPK in RPE cells using Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 did not abolish the inhibitory effects of AICAR on RPE CFB expression. Collectively, our results suggest that AICAR can suppress TNF-α-induced CFB expression in RPE cells in an AMPK-independent mechanism, and could be used as a therapeutic target in certain complement over-activation scenarios. |
format | Online Article Text |
id | pubmed-5732305 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57323052017-12-21 AICAR suppresses TNF-α-induced complement factor B in RPE cells Chung, Eun Jee Efstathiou, Nikolaos E. Konstantinou, Eleni K. Maidana, Daniel E. Miller, Joan W. Young, Lucy H. Vavvas, Demetrios G. Sci Rep Article Age related macular degeneration is the leading cause of blindness in the developed world. Although its precise cause remains elusive, dysfunction of the retinal pigment epithelium (RPE) and dysregulation of complement have been implicated in its pathogenesis. The goal of this study was to evaluate the role of an AMP-dependent kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), on tumor necrosis factor alpha (TNF-α) induction of complement factor B (CFB) in RPE cells. We found that AICAR inhibited TNF-α-induced CFB expression in ARPE-19 and human primary RPE cells in a dose-dependent fashion. Treatment of cells with dipyridamole, which blocks AICAR cellular uptake abolished these effects. In contrast, the adenosine kinase inhibitor, 5-iodotubericidin, which inhibits the conversion of AICAR to the direct activator of AMPK, ZMP, did not reverse the effects on TNF-α-induced CFB expression, suggesting AMPK-independent effects. Indeed, knockout of AMPK in RPE cells using Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 did not abolish the inhibitory effects of AICAR on RPE CFB expression. Collectively, our results suggest that AICAR can suppress TNF-α-induced CFB expression in RPE cells in an AMPK-independent mechanism, and could be used as a therapeutic target in certain complement over-activation scenarios. Nature Publishing Group UK 2017-12-15 /pmc/articles/PMC5732305/ /pubmed/29247196 http://dx.doi.org/10.1038/s41598-017-17744-w Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Chung, Eun Jee Efstathiou, Nikolaos E. Konstantinou, Eleni K. Maidana, Daniel E. Miller, Joan W. Young, Lucy H. Vavvas, Demetrios G. AICAR suppresses TNF-α-induced complement factor B in RPE cells |
title | AICAR suppresses TNF-α-induced complement factor B in RPE cells |
title_full | AICAR suppresses TNF-α-induced complement factor B in RPE cells |
title_fullStr | AICAR suppresses TNF-α-induced complement factor B in RPE cells |
title_full_unstemmed | AICAR suppresses TNF-α-induced complement factor B in RPE cells |
title_short | AICAR suppresses TNF-α-induced complement factor B in RPE cells |
title_sort | aicar suppresses tnf-α-induced complement factor b in rpe cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732305/ https://www.ncbi.nlm.nih.gov/pubmed/29247196 http://dx.doi.org/10.1038/s41598-017-17744-w |
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