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Published online 10 April 2006 doi:10.1084/jem.20050625
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 973-984
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ARTICLE

 Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells

Michael Lotz1, Dominique Gütle1, Sabrina Walther1, Sandrine Ménard1,2, Christian Bogdan1, and Mathias W. Hornef1,2

1 Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany
2 Swedish Institute for Infectious Diseases Control, 17177 Stockholm, Sweden

CORRESPONDENCE Mathias W. Hornef: mathias.hornef{at}uniklinik-freiburg.de

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 {kappa}B (NF-{kappa}B) 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 I{kappa}B-{alpha} and nuclear translocation of NF-{kappa}B 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.

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.


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