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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17 April 2006
Article|
April 10 2006
Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells
Michael Lotz,
Michael Lotz
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
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Dominique Gütle,
Dominique Gütle
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
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Sabrina Walther,
Sabrina Walther
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
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Sandrine Ménard,
Sandrine Ménard
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
2Swedish Institute for Infectious Diseases Control, 17177 Stockholm, Sweden
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Christian Bogdan,
Christian Bogdan
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
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Mathias W. Hornef
Mathias W. Hornef
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
2Swedish Institute for Infectious Diseases Control, 17177 Stockholm, Sweden
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Michael Lotz
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
Dominique Gütle
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
Sabrina Walther
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
Sandrine Ménard
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
2Swedish Institute for Infectious Diseases Control, 17177 Stockholm, Sweden
Christian Bogdan
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
Mathias W. Hornef
1Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
2Swedish Institute for Infectious Diseases Control, 17177 Stockholm, Sweden
CORRESPONDENCE Mathias W. Hornef: [email protected]
Abbreviations used: HPRT, hypoxanthine phosphoribosyltransferase; IEC, intestinal epithelial cell; IRAK, IL-1 receptor–associated kinase 1; MIP-2, macrophage inflammatory protein 2; NEC, necrotizing enterocolitis; RQ, relative quantity; TLR, Toll-like receptor; ZO, zonula occludens protein.
Received:
March 25 2005
Accepted:
March 10 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2006
J Exp Med (2006) 203 (4): 973–984.
Article history
Received:
March 25 2005
Accepted:
March 10 2006
Connected Content
Citation
Michael Lotz, Dominique Gütle, Sabrina Walther, Sandrine Ménard, Christian Bogdan, Mathias W. Hornef; Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells . J Exp Med 17 April 2006; 203 (4): 973–984. doi: https://doi.org/10.1084/jem.20050625
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