Postnatal Acquisition of Endotoxin Tolerance in Intestinal Epithelial Cells

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2006 Apr 12

PMID 16606665

Citations 186

Authors

Michael Lotz

Dominique Gutle

Sabrina Walther

Sandrine Menard

Christian Bogdan

Mathias W Hornef

Affiliations

Soon will be listed here.

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.

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References

Zhang D, Zhang G, Hayden M, Greenblatt M, Bussey C, Flavell R . A toll-like receptor that prevents infection by uropathogenic bacteria. Science. 2004; 303(5663):1522-6. DOI: 10.1126/science.1094351. View

Naik S, Kelly E, Meijer L, Pettersson S, Sanderson I . Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr. 2001; 32(4):449-53. DOI: 10.1097/00005176-200104000-00011. View

Kanakaraj P, Ngo K, Wu Y, Angulo A, Ghazal P, Harris C . Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J Exp Med. 1999; 189(7):1129-38. PMC: 2193007. DOI: 10.1084/jem.189.7.1129. View

Hsueh W, Caplan M, Qu X, Tan X, De Plaen I, GONZALEZ-CRUSSI F . Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol. 2002; 6(1):6-23. PMC: 7098425. DOI: 10.1007/s10024-002-0602-z. View

Abreu M, Vora P, Faure E, Thomas L, Arnold E, Arditi M . Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol. 2001; 167(3):1609-16. DOI: 10.4049/jimmunol.167.3.1609. View

Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R . Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004; 118(2):229-41. DOI: 10.1016/j.cell.2004.07.002. View

Smythies L, Sellers M, Clements R, Mosteller-Barnum M, Meng G, Benjamin W . Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest. 2005; 115(1):66-75. PMC: 539188. DOI: 10.1172/JCI19229. View

Andonegui G, Bonder C, Green F, Mullaly S, Zbytnuik L, Raharjo E . Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest. 2003; 111(7):1011-20. PMC: 152584. DOI: 10.1172/JCI16510. View

Thomas J, Allen J, Tsen M, Dubnicoff T, Danao J, Liao X . Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J Immunol. 1999; 163(2):978-84. View

10.

Hooper L, Xu J, Falk P, Midtvedt T, Gordon J . A molecular sensor that allows a gut commensal to control its nutrient foundation in a competitive ecosystem. Proc Natl Acad Sci U S A. 1999; 96(17):9833-8. PMC: 22296. DOI: 10.1073/pnas.96.17.9833. View

11.

Fukata M, Michelsen K, Eri R, Thomas L, Hu B, Lukasek K . Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol. 2005; 288(5):G1055-65. DOI: 10.1152/ajpgi.00328.2004. View

12.

Chan K, Ho J, Chan K, Tam P . A study of gut immunity to enteral endotoxin in rats of different ages: a possible cause for necrotizing enterocolitis. J Pediatr Surg. 2002; 37(10):1435-40. DOI: 10.1053/jpsu.2002.35407. View

13.

Jacinto R, Hartung T, McCall C, Li L . Lipopolysaccharide- and lipoteichoic acid-induced tolerance and cross-tolerance: distinct alterations in IL-1 receptor-associated kinase. J Immunol. 2002; 168(12):6136-41. DOI: 10.4049/jimmunol.168.12.6136. View

14.

Janssens S, Beyaert R . Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol Cell. 2003; 11(2):293-302. DOI: 10.1016/s1097-2765(03)00053-4. View

15.

Edwards C, Parrett A . Intestinal flora during the first months of life: new perspectives. Br J Nutr. 2002; 88 Suppl 1:S11-8. DOI: 10.1079/BJN2002625. View

16.

Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, Tschopp J . Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med. 2003; 197(2):263-8. PMC: 2193806. DOI: 10.1084/jem.20021790. View

17.

Bens M, Bogdanova A, Cluzeaud F, Miquerol L, Kerneis S, Kraehenbuhl J . Transimmortalized mouse intestinal cells (m-ICc12) that maintain a crypt phenotype. Am J Physiol. 1996; 270(6 Pt 1):C1666-74. DOI: 10.1152/ajpcell.1996.270.6.C1666. View

18.

Medzhitov R . Toll-like receptors and innate immunity. Nat Rev Immunol. 2002; 1(2):135-45. DOI: 10.1038/35100529. View

19.

Sato S, Takeuchi O, Fujita T, Tomizawa H, Takeda K, Akira S . A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways. Int Immunol. 2002; 14(7):783-91. DOI: 10.1093/intimm/dxf046. View

20.

Hornef M, Henriques Normark B, Vandewalle A, Normark S . Intracellular recognition of lipopolysaccharide by toll-like receptor 4 in intestinal epithelial cells. J Exp Med. 2003; 198(8):1225-35. PMC: 2194240. DOI: 10.1084/jem.20022194. View