Cargando…

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....

Descripción completa

Detalles Bibliográficos
Autores principales: Guiducci, Cristiana, Ghirelli, Cristina, Marloie-Provost, Marie-Annick, Matray, Tracy, Coffman, Robert L., Liu, Yong-Jun, Barrat, Franck J., Soumelis, Vassili
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
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
_version_ 1782151786487873536
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
work_keys_str_mv AT guiduccicristiana pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT ghirellicristina pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT marloieprovostmarieannick pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT matraytracy pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT coffmanrobertl pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT liuyongjun pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT barratfranckj pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation
AT soumelisvassili pi3kiscriticalforthenucleartranslocationofirf7andtypeiifnproductionbyhumanplasmacytoidpredendriticcellsinresponsetotlractivation