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PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation
Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known....
Autores principales: | , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271003/ https://www.ncbi.nlm.nih.gov/pubmed/18227218 http://dx.doi.org/10.1084/jem.20070763 |
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author | Guiducci, Cristiana Ghirelli, Cristina Marloie-Provost, Marie-Annick Matray, Tracy Coffman, Robert L. Liu, Yong-Jun Barrat, Franck J. Soumelis, Vassili |
author_facet | Guiducci, Cristiana Ghirelli, Cristina Marloie-Provost, Marie-Annick Matray, Tracy Coffman, Robert L. Liu, Yong-Jun Barrat, Franck J. Soumelis, Vassili |
author_sort | Guiducci, Cristiana |
collection | PubMed |
description | Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor α and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K δ subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor κB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases. |
format | Text |
id | pubmed-2271003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-22710032008-08-18 PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation Guiducci, Cristiana Ghirelli, Cristina Marloie-Provost, Marie-Annick Matray, Tracy Coffman, Robert L. Liu, Yong-Jun Barrat, Franck J. Soumelis, Vassili J Exp Med Brief Definitive Reports Plasmacytoid predendritic cells (pDCs) are the main producers of type I interferon (IFN) in response to Toll-like receptor (TLR) stimulation. Phosphatidylinositol-3 kinase (PI3K) has been shown to be activated by TLR triggering in multiple cell types; however, its role in pDC function is not known. We show that PI3K is activated by TLR stimulation in primary human pDCs and demonstrate, using specific inhibitors, that PI3K is required for type I IFN production by pDCs, both at the transcriptional and protein levels. Importantly, PI3K was not involved in other proinflammatory responses of pDCs, including tumor necrosis factor α and interleukin 6 production and DC differentiation. pDCs preferentially expressed the PI3K δ subunit, which was specifically involved in the control of type I IFN production. Although uptake and endosomal trafficking of TLR ligands were not affected in the presence of PI3K inhibitors, there was a dramatic defect in the nuclear translocation of IFN regulatory factor (IRF) 7, whereas nuclear factor κB activation was preserved. Thus, PI3K selectively controls type I IFN production by regulating IRF-7 nuclear translocation in human pDCs and could serve as a novel target to inhibit pathogenic type I IFN in autoimmune diseases. The Rockefeller University Press 2008-02-18 /pmc/articles/PMC2271003/ /pubmed/18227218 http://dx.doi.org/10.1084/jem.20070763 Text en Copyright © 2008, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Reports Guiducci, Cristiana Ghirelli, Cristina Marloie-Provost, Marie-Annick Matray, Tracy Coffman, Robert L. Liu, Yong-Jun Barrat, Franck J. Soumelis, Vassili PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation |
title | PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation |
title_full | PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation |
title_fullStr | PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation |
title_full_unstemmed | PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation |
title_short | PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation |
title_sort | pi3k is critical for the nuclear translocation of irf-7 and type i ifn production by human plasmacytoid predendritic cells in response to tlr activation |
topic | Brief Definitive Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271003/ https://www.ncbi.nlm.nih.gov/pubmed/18227218 http://dx.doi.org/10.1084/jem.20070763 |
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