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Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels

AU-rich elements (AREs) are cis-acting instability and translation inhibition elements that are present in the 3ʹUTR of most inducible inflammatory mRNAs such as TNF and Cxcl2. mRNAs that contain AREs are, by default, repressed and only transiently expressed in response to stimuli. They are targeted...

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Autores principales: Mahmoud, Linah, Moghrabi, Walid, Khabar, Khalid S. A., Hitti, Edward G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380337/
https://www.ncbi.nlm.nih.gov/pubmed/30664390
http://dx.doi.org/10.1080/15476286.2019.1572437
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author Mahmoud, Linah
Moghrabi, Walid
Khabar, Khalid S. A.
Hitti, Edward G.
author_facet Mahmoud, Linah
Moghrabi, Walid
Khabar, Khalid S. A.
Hitti, Edward G.
author_sort Mahmoud, Linah
collection PubMed
description AU-rich elements (AREs) are cis-acting instability and translation inhibition elements that are present in the 3ʹUTR of most inducible inflammatory mRNAs such as TNF and Cxcl2. mRNAs that contain AREs are, by default, repressed and only transiently expressed in response to stimuli. They are targeted by the inducible RNA-binding protein Tristetraprolin (TTP) which blocks their translation and facilitates their decay, thereby contributing to the quick termination of their expression. The exogenous over-expression of TTP in HEK293 cells can unexpectedly lead to the upregulation and extended expression of a nanoLuciferase reporter that contains the ARE of TNF. Here we show that, a moderate downregulation of the highly expressed endogenous TTP after LPS induction by siRNA in macrophages can lead to a reduction in the release of TNF and Cxcl2. We propose that, in contrast to their canonical function, very high levels of induced TTP at the onset of the inflammatory response can enhance the expression of ARE-mRNAs at the post-transcriptional level, independently of phosphorylation status. As the inflammatory response progresses, TTP levels diminish but they continuously regain their ability to reduce the expression of ARE-mRNAs to reach a turning point of ‘optimal TTP level’ with a maximum ability to repress ARE-mRNA expression. Below this level, a further reduction in TTP levels now leads to the loss of canonical-TTP function resulting in increased ARE-mRNA expression. These novel findings should contribute to the understanding of feedback loops that control the kinetics of the inflammatory response.
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spelling pubmed-63803372019-02-25 Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels Mahmoud, Linah Moghrabi, Walid Khabar, Khalid S. A. Hitti, Edward G. RNA Biol Research Paper AU-rich elements (AREs) are cis-acting instability and translation inhibition elements that are present in the 3ʹUTR of most inducible inflammatory mRNAs such as TNF and Cxcl2. mRNAs that contain AREs are, by default, repressed and only transiently expressed in response to stimuli. They are targeted by the inducible RNA-binding protein Tristetraprolin (TTP) which blocks their translation and facilitates their decay, thereby contributing to the quick termination of their expression. The exogenous over-expression of TTP in HEK293 cells can unexpectedly lead to the upregulation and extended expression of a nanoLuciferase reporter that contains the ARE of TNF. Here we show that, a moderate downregulation of the highly expressed endogenous TTP after LPS induction by siRNA in macrophages can lead to a reduction in the release of TNF and Cxcl2. We propose that, in contrast to their canonical function, very high levels of induced TTP at the onset of the inflammatory response can enhance the expression of ARE-mRNAs at the post-transcriptional level, independently of phosphorylation status. As the inflammatory response progresses, TTP levels diminish but they continuously regain their ability to reduce the expression of ARE-mRNAs to reach a turning point of ‘optimal TTP level’ with a maximum ability to repress ARE-mRNA expression. Below this level, a further reduction in TTP levels now leads to the loss of canonical-TTP function resulting in increased ARE-mRNA expression. These novel findings should contribute to the understanding of feedback loops that control the kinetics of the inflammatory response. Taylor & Francis 2019-01-28 /pmc/articles/PMC6380337/ /pubmed/30664390 http://dx.doi.org/10.1080/15476286.2019.1572437 Text en © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Research Paper
Mahmoud, Linah
Moghrabi, Walid
Khabar, Khalid S. A.
Hitti, Edward G.
Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels
title Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels
title_full Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels
title_fullStr Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels
title_full_unstemmed Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels
title_short Bi-phased regulation of the post-transcriptional inflammatory response by Tristetraprolin levels
title_sort bi-phased regulation of the post-transcriptional inflammatory response by tristetraprolin levels
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380337/
https://www.ncbi.nlm.nih.gov/pubmed/30664390
http://dx.doi.org/10.1080/15476286.2019.1572437
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