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Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells

The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccha...

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Autores principales: Lotz, Michael, Gütle, Dominique, Walther, Sabrina, Ménard, Sandrine, Bogdan, Christian, Hornef, Mathias W.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118301/
https://www.ncbi.nlm.nih.gov/pubmed/16606665
http://dx.doi.org/10.1084/jem.20050625
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author Lotz, Michael
Gütle, Dominique
Walther, Sabrina
Ménard, Sandrine
Bogdan, Christian
Hornef, Mathias W.
author_facet Lotz, Michael
Gütle, Dominique
Walther, Sabrina
Ménard, Sandrine
Bogdan, Christian
Hornef, Mathias W.
author_sort Lotz, Michael
collection PubMed
description The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccharide (LPS) receptor complex TLR4/MD-2 was present in fetal, neonatal, and adult IECs, LPS-induced nuclear factor κB (NF-κB) activation and chemokine (macrophage inflammatory protein 2 [MIP-2]) secretion was only detected in fetal IECs. Fetal intestinal macrophages, in contrast, were constitutively nonresponsive to LPS. Acquisition of LPS resistance was paralleled by a spontaneous activation of IECs shortly after birth as illustrated by phosphorylation of IκB-α and nuclear translocation of NF-κB p65 in situ as well as transcriptional activation of MIP-2. Importantly, the spontaneous IEC activation occurred in vaginally born mice but not in neonates delivered by Caesarean section or in TLR4-deficient mice, which together with local endotoxin measurements identified LPS as stimulatory agent. The postnatal loss of LPS responsiveness of IECs was associated with a posttranscriptional down-regulation of the interleukin 1 receptor–associated kinase 1, which was essential for epithelial TLR4 signaling in vitro. Thus, unlike intestinal macrophages, IECs acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host–microbe homeostasis.
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spelling pubmed-21183012007-12-13 Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells Lotz, Michael Gütle, Dominique Walther, Sabrina Ménard, Sandrine Bogdan, Christian Hornef, Mathias W. J Exp Med Articles The role of innate immune recognition by intestinal epithelial cells (IECs) in vivo is ill-defined. Here, we used highly enriched primary IECs to analyze Toll-like receptor (TLR) signaling and mechanisms that prevent inappropriate stimulation by the colonizing microflora. Although the lipopolysaccharide (LPS) receptor complex TLR4/MD-2 was present in fetal, neonatal, and adult IECs, LPS-induced nuclear factor κB (NF-κB) activation and chemokine (macrophage inflammatory protein 2 [MIP-2]) secretion was only detected in fetal IECs. Fetal intestinal macrophages, in contrast, were constitutively nonresponsive to LPS. Acquisition of LPS resistance was paralleled by a spontaneous activation of IECs shortly after birth as illustrated by phosphorylation of IκB-α and nuclear translocation of NF-κB p65 in situ as well as transcriptional activation of MIP-2. Importantly, the spontaneous IEC activation occurred in vaginally born mice but not in neonates delivered by Caesarean section or in TLR4-deficient mice, which together with local endotoxin measurements identified LPS as stimulatory agent. The postnatal loss of LPS responsiveness of IECs was associated with a posttranscriptional down-regulation of the interleukin 1 receptor–associated kinase 1, which was essential for epithelial TLR4 signaling in vitro. Thus, unlike intestinal macrophages, IECs acquire TLR tolerance immediately after birth by exposure to exogenous endotoxin to facilitate microbial colonization and the development of a stable intestinal host–microbe homeostasis. The Rockefeller University Press 2006-04-17 /pmc/articles/PMC2118301/ /pubmed/16606665 http://dx.doi.org/10.1084/jem.20050625 Text en Copyright © 2006, 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 Articles
Lotz, Michael
Gütle, Dominique
Walther, Sabrina
Ménard, Sandrine
Bogdan, Christian
Hornef, Mathias W.
Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
title Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
title_full Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
title_fullStr Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
title_full_unstemmed Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
title_short Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
title_sort postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118301/
https://www.ncbi.nlm.nih.gov/pubmed/16606665
http://dx.doi.org/10.1084/jem.20050625
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