title: Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells.
abstract: 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 kappaB (NF-kappaB) 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 IkappaB-alpha and nuclear translocation of NF-kappaB 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.
authors.affiliation: Department for Medical Microbiology and Hygiene, University Clinic of Freiburg, 79104 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lotz
authors.forename: Dominique
authors.initials: D
authors.lastname: Gütle
authors.forename: Sabrina
authors.initials: S
authors.lastname: Walther
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ménard
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D004731:Endotoxins / Q000276:immunology* / Q000633:toxicity; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D004731:Endotoxins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases