“For Whom the Bell Tolls!” - Innate Defense   Mechanisms and Survival Strategies of the Intestinal Epithelium Against Lumenal   Pathogens

E. Cario; G. Gerken; D. K. Podolsky

doi:10.1055/s-2002-36159

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2002; 40(12): 983-990
DOI: 10.1055/s-2002-36159

Übersicht

“For Whom the Bell Tolls!” - Innate Defense Mechanisms and Survival Strategies of the Intestinal Epithelium Against Lumenal Pathogens

„Wem die Stunde schlägt!” - Angeborene Verteidigungs- und Überlebensstrategien des intestinalen Epithels gegen pathogene Mikroben des LumensE. Cario¹ , G. Gerken¹ , D. K. Podolsky²

¹Division of Gastroenterology & Hepatology, University of Essen, Essen, Germany
²Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA

Abstract

Zusammenfassung

Das intestinale Epithel ist zentraler Bestandteil der defensiven Schutzbarriere des mukosalen Immunsystems - mit einer bipolaren Grenzfläche zwischen zahlreichen lumenalen Mikroben einerseits und Immunzellen der Lamina propria andererseits. Intestinale Epithelzellen exprimieren verschiedene “pattern recognition receptors”, die zur frühzeitigen Erkennung von “pathogen-associated molecular patterns” als „fremd” dienen und gezielte angeborene Immunantworten zur Verteidigung initiieren. Es wird hier das derzeitige Verständnis zusammengefasst, wie das intestinale Epithel mit verschiedenen angeborenen Immuneigenschaften lumenale Homöostase sichert, und es wird diskutiert, wie deren Dysregulation eine zentrale pathogenetische Rolle in der überschießenden Immunantwort bei chronisch-entzündlichen Darmerkrankungen spielen könnte.

Abstract

The intestinal epithelium serves as an essential defensive barrier of the mucosal immune system that forms a bipolar interface between the diverse populations of microbes of the lumen and subjacent immune cells present in the lamina propria. Intestinal epithelial cells express various pattern recognition receptors - poised to recognize microbial “pathogen-associated molecular patterns” as “non-self” and to rapidly initiate innate immune responses of survival and active defense strategies against lumenal pathogens. Current understanding of the variety of innate immune features present in intestinal epithelium to maintain homeostasis is summarized and the mechanisms through which dysregulation may play a central role in initiation and perpetuation of inflammatory bowel disease are discussed.

Schlüsselwöter

Angeborene Immunität - Intestinales Epithel - Wirtsverteidigung - Mukosa - Toll-like Rezeptoren - Nods - Apoptose

Key words

Innate immunity - intestinal epithelium - host defense - mucosa - toll-like receptors - nods - apoptosis

Full Text

References

1 MacDonald T T, Pettersson S. Bacterial regulation of intestinal immune responses. Inflamm Bowel Dis. 2000; 6 116-122
2 Podolsky D K. Mucosal immunity and inflammation. V. Innate mechanisms of mucosal defense and repair: the best offense is a good defense. Am J Physiol. 1999; 277 G495-499
3 Hecht G. Innate mechanisms of epithelial host defense: spotlight on intestine. Am J Physiol. 1999; 277 C351-C358
4 Podolsky D K, Lynch-Devaney K, Stow J L. et al . Identification of human intestinal trefoil factor. Goblet cell-specific expression of a peptide targeted for apical secretion. J Biol Chem. 1993; 268 6694-6702
5 Andoh A, Kinoshita K, Rosenberg I. et al . Intestinal trefoil factor induces decay-accelerating factor expression and enhances the protective activities against complement activation in intestinal epithelial cells. J Immunol. 2001; 167 3887-3893
6 O’Neil D A, Porter E M, Elewaut D. et al . Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium. J Immunol. 1999; 163 6718-6724
7 Hase K, Eckmann L, Leopard J D. et al . Cell Differentiation Is a Key Determinant of Cathelicidin LL-37/Human Cationic Antimicrobial Protein 18 Expression by Human Colon Epithelium. Infect Immun. 2002; 70 953-963
8 Kawasaki Y, Tazume S, Shimizu K. et al . Inhibitory effects of bovine lactoferrin on the adherence of enterotoxigenic Escherichia coli to host cells. Biosci Biotechnol Biochem. 2000; 64 348-354
9 Kruzel M L, Harari Y, Chen C Y. et al . Lactoferrin protects gut mucosal integrity during endotoxemia induced by lipopolysaccharide in mice. Inflammation. 2000; 24 33-44
10 Santini D, Pasquinelli G, Mazzoleni G. et al . Lysozyme localization in normal and diseased human gastric and colonic mucosa. A correlative histochemical, immunohistochemical and immunoelectron microscopic investigation. Apmis. 1992; 100 575-585
11 Grossman E M, Longo W E, Mazuski J E. et al . Role of cytoplasmic and secretory phospholipase A2 in intestinal epithelial cell prostaglandin E2 formation. Int J Surg Investig. 2000; 1 467-476
12 Schultsz C, Van Den Berg F M, Ten K ate FW. et al . The intestinal mucus layer from patients with inflammatory bowel disease harbors high numbers of bacteria compared with controls. Gastroenterology. 1999; 117 1089-1097
13 Sudha P S, Devaraj H, Devaraj N. Adherence of Shigella dysenteriae 1 to human colonic mucin. Curr Microbiol. 2001; 42 381-387
14 Mantle M, Rombough C. Growth in and breakdown of purified rabbit small intestinal mucin by Yersinia enterocolitica. Infect Immun. 1993; 61 4131-4138
15 Janeway C A Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002; 20 197-216
16 Beatty W L, Meresse S, Gounon P. et al . Trafficking of Shigella lipopolysaccharide in polarized intestinal epithelial cells. J Cell Biol. 1999; 145 689-698
17 Hornef M W, Frisan T, Vandewalle A. et al . Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells. J Exp Med. 2002; 195 559-570
18 Cario E, Brown D, McKee M. et al . Commensal-associated molecular patterns induce selective toll-like receptor-trafficking from apical membrane to cytoplasmic compartments in polarized intestinal epithelium. Am J Pathol. 2002; 160 165-173
19 Medzhitov R, Janeway C A. Innate Immunity. N Engl J Med. 2000; 343 338-344
20 Pugin J, Schurer-Maly C C, Leturcq D. et al . Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci U S A. 1993; 90 2744-2748
21 Cario E, Rosenberg I M, Brandwein S L. et al . Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J Immunol. 2000; 164 966-972
22 Funda D P, Tuckova L, Farre M A. et al . CD14 is expressed and released as soluble CD14 by human intestinal epithelial cells in vitro: lipopolysaccharide activation of epithelial cells revisited. Infect Immun. 2001; 69 3772-3781
23 Martin-Villa J M, Ferre-Lopez S, Lopez-Suarez J C. et al . Cell surface phenotype and ultramicroscopic analysis of purified human enterocytes: a possible antigen-presenting cell in the intestine. Tissue Antigens. 1997; 50 586-592
24 Meijssen M A, Brandwein S L, Reinecker H C. et al . Alteration of gene expression by intestinal epithelial cells precedes colitis in interleukin-2-deficient mice. Am J Physiol. 1998; 274 G472-479
25 Labeta M O, Vidal K, Nores J E. et al . Innate recognition of bacteria in human milk is mediated by a milk-derived highly expressed pattern recognition receptor, soluble CD14. J Exp Med. 2000; 191 1807-1812
26 Uehara A, Sugawara S, Tamai R. et al . Contrasting responses of human gingival and colonic epithelial cells to lipopolysaccharides, lipoteichoic acids and peptidoglycans in the presence of soluble CD14. Med Microbiol Immunol (Berl). 2001; 189 185-192
27 Schumann R R, Zweigner J. A novel acute-phase marker: lipopolysaccharide binding protein (LBP). Clin Chem Lab Med. 1999; 37 271-274
28 Le R oy D, Di Padova F, Tees R. et al . Monoclonal antibodies to murine lipopolysaccharide (LPS)-binding protein (LBP) protect mice from lethal endotoxemia by blocking either the binding of LPS to LBP or the presentation of LPS/LBP complexes to CD14. J Immunol. 1999; 162 7454-7460
29 Lamping N, Dettmer R, Schroder N W. et al . LPS-binding protein probtects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest. 1998; 101 2065-2071
30 Zweigner J, Gramm H J, Singer O C. et al . High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes. Blood. 2001; 98 3800-3808
31 Vreugdenhil A C, Snoek A M, Greve J W. et al . Lipopolysaccharide-binding protein is vectorially secreted and transported by cultured intestinal epithelial cells and is present in the intestinal mucus of mice. J Immunol. 2000; 165 4561-4566
32 Girardin S E, Tournebize R, Mavris M. et al . CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2001; 2 736-742
33 Philpott D J, Girardin S E, Sansonetti P J. Innate immune responses of epithelial cells following infection with bacterial pathogens. Curr Opin Immunol. 2001; 13 410-416
34 Inohara N, Ogura Y, Chen F F. et al . Human nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem. 2001; 276 2551-2554
35 Inohara N, Nunez G. The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene. 2001; 20 6473-6481
36 Hisamatsu T, Suzuki M, Reinecker H C. et al . NOD1 and NOD2, cytoplasmic LPS receptors, are expressed in intestinal epithelial cells and regulated by proinflammatory cytokines. Gastroenterology (Abstract-DDW2002). 2002; in press
37 Ogura Y, Bonen D K, Inohara N. et al . A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001; 411 603-608
38 Hugot J P, Chamalliard M, Zouali H. et al . Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001; 411 599-603
39 Hampe J, Cuthbert A, Croucher P J. et al . Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet. 2001; 357 1925-1928
40 Hampe J, Frenzel H, Mirza M M. et al . Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc Natl Acad Sci U S A. 2002; 99 321-326
41 Cario E, Podolsky D K. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect Immun. 2000; 68 7010-7017
42 Fusunyan R D, Nanthakumar N N, Baldeon M E. et al . Evidence for an innate immune response in the immature human intestine: Toll-like receptors on fetal enterocytes. Pediatric Res. 2001; 49 589-593
43 Gewirtz A T, Navas T A, Lyons S. et al . Cutting edge: bacterial flagellin activates basolaterally expressed tlr5 to induce epithelial proinflammatory gene expression. J Immunol. 2001; 167 1882-1885
44 Abreu M T, Vora P, Faure E. et al . 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 1609-1616
45 Kawahara T, Kuwano Y, Teshima-Kondo S. et al . Helicobacter pylori lipopolysaccharide from type I, but not type II strains, stimulates apoptosis of cultured gastric mucosal cells. J Med Invest. 2001; 48 167-174
46 Kawahara T, Kuwano Y, Teshima-Kondo S. et al . Toll-like receptor 4 regulates gastric pit cell responses to Helicobacter pylori infection. J Med Invest. 2001; 48 190-197
47 Lien E, Ingalls R R. Toll-like receptors. Crit Care Med. 2002; 30 S1-S11
48 Zarember K A, Godowski P J. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002; 168 554-561
49 Muzio M, Bosisio D, Polentarutti N. et al . Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol. 2000; 164 5998-6004
50 Visintin A, Mazzoni A, Spitzer J H. et al . Regulation of Toll-like receptors in human monocytes and dendritic cells. J Immunol. 2001; 166 249-255
51 Bogunovic M, Reka S, Evans K N. et al . Functional Toll-like receptors (TLR) are expressed on intestinal epithelial cells (IEC). Gastroenterology. 2000; 118 A804 (abstract)
52 Naik S, Kelly E J, Meijer L. et al . Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr. 2001; 32 449-453
53 Smith P D, Smythies L E, Mosteller-Barnum M. et al . Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities. J Immunol. 2001; 167 2651-2656
54 Hausmann M, Spoettl T, Schoelmerich J. et al . Induction of Toll-like Receptor 2 in human intestinal myofibroblasts by interferon gamma. Gastroenterology. 2000; 118 A791 (abstract)
55 Hertz C J, Kiertscher S M, Godowski P J. et al . Microbial lipopeptides stimulate dendritic cell maturation via Toll-like receptor 2. J Immunol. 2001; 166 2444-2450
56 Takeuchi O, Hoshino K, Kawai T. et al . Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity. 1999; 11 443-451
57 Wang Q, Dziarski R, Kirschning C J. et al . Micrococci and peptidoglycan activate TLR2->MyD88->IRAK->TRAF->NIK->IKK->NF-kappaB signal transduction pathway that induces transcription of interleukin-8. Infect Immun. 2001; 69 2270-2276
58 Bulut Y, Faure E, Thomas L. et al . Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J Immunol. 2001; 167 987-994
59 Ozinsky A, Underhill D M, Fontenot J D. et al . The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA. 2000; 97 13766-13771
60 Wyllie D H, Kiss-Toth E, Visintin A. et al . Evidence for an accessory protein function for Toll-like receptor 1 in anti-bacterial responses. J Immunol. 2000; 165 7125-7132
61 Edwards E W, Bogunovic M, Yager J. et al . Toll-like receptor expression and function in intestinal epithelial cells: An epithelial cell type co-expressing TLR1 and TLR2. FASEB. 2001; (Abstract)
62 Hajjar A M, O’Mahony D S, Ozinsky A. et al . Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J Immunol. 2001; 166 15-19
63 Alexopoulou L, Holt A C, Medzhitov R. et al . Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001; 413 732-738
64 Hemmi H, Kaisho T, Takeuchi O. et al . Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002; 3 196-200
65 Reed K A, Hobert M E, Kolenda C E. et al . The Salmonella typhimurium flagellar basal body protein FliE is required for flagellin production and to induce a pro-inflammatory response in epithelial cells. J Biol Chem. 2002; 30 30
66 Hemmi H, Takeuchi O, Kawai T. et al . A Toll-like receptor recognizes bacterial DNA. Nature. 2000; 408 740-745
67 Hoshino K, Takeuchi O, Kawai T. et al . Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol. 1999; 162 3749-3752
68 Kawasaki K, Akashi S, Shimazu R. et al . Involvement of TLR4/MD-2 complex in species-specific lipopolysaccharide-mimetic signal transduction by Taxol. J Endotoxin Res. 2001; 7 232-236
69 Perera P Y, Mayadas T N, Takeuchi O. et al . CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol. 2001; 166 574-581
70 Tapping R I, Akashi S, Miyake K. et al . Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. J Immunol. 2000; 165 5780-5787
71 Visintin A, Mazzoni A, Spitzer J A. et al . Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4. Proc Natl Acad Sci USA. 2001; 98 12156-12161
72 Viriyakosol S, Kirkland T, Soldau K. et al . MD-2 binds to bacterial lipopolysaccharide. J Endotoxin Res. 2000; 6 489-491
73 Hume D A, Underhill D M, Sweet M J. et al . Macrophages exposed continuously to lipopolysaccharide and other agonists that act via toll-like receptors exhibit a sustained and additive activation state. BMC Immunol. 2001; 2 11
74 Xu Y, Tao X, Shen B. et al . Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature. 2000; 408 111-115
75 Lazou A hren I, Bjartell A, Egesten A. et al . Lipopolysaccharide-binding protein increases toll-like receptor 4-dependent activation by nontypeable Haemophilus influenzae. J Infect Dis. 2001; 184 926-930
76 Vogel S, Hirschfeld M J, Perera P Y. Signal integration in lipopolysaccharide (LPS)-stimulated murine macrophages. J Endotoxin Res. 2001; 7 237-241
77 Bainbridge B W, Darveau R P. Porphyromonas gingivalis lipopolysaccharide: an unusual pattern recognition receptor ligand for the innate host defense system. Acta Odontol Scand. 2001; 59 131-138
78 Netea M G, van Deuren M, Kullberg B J. et al . Does the shape of lipid A determine the interaction of LPS with Toll-like receptors?. Trends Immunol. 2002; 23 135-139
79 Asea A, Rehli M, Kabingu E. et al . Novel signal transduction pathway utilized by extracellular HSP70: Role of TLR2 and TLR4. J Biol Chem. 2002; 8 8
80 Vabulas R M, Ahmad-Nejad P, da Costa C. et al . Endocytosed HSP60 s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem. 2001; 276 31332-31339
81 Okamura Y, Watari M, Jerud E S. et al . The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001; 276 10229-10233
82 Roger T, David J, Glauser M P. et al . MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature. 2001; 414 920-924
83 Suzuki M, Podolsky D K. Differential regulation of Toll-like receptors by pro- and anti-inflammatory cytokines between human intestinal epithelial and monocytic cell lines. Gastroenterology. 2001; 120 A-326 (abstract)
84 Randow F, Seed B. Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat Cell Biol. 2001; 3 891-896
85 Underhill D M, Ozinsky A, Hajjar A M. et al . The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature. 1999; 401 811-815
86 Hacker H, Vabulas R M, Takeuchi O. et al . Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J Exp Med. 2000; 192 595-600
87 Kaisho T, Takeuchi O, Kawai T. et al . Endotoxin-induced maturation of myd88-deficient dendritic cells. J Immunol. 2001; 166 5688-5694
88 Zhang F X, Kirschning C J, Mancinelli R. et al . Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem. 1999; 274 7611-7614
89 Faure E, Equils O, Sieling P A. et al . Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem. 2000; 275 11058-11063
90 Schnare M, Barton G M, Holt A C. et al . Toll-like receptors control activation of adaptive immune responses. Nat Immunol. 2001; 2 947-950
91 Burns K, Clatworthy J, Martin L. et al . Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol. 2000; 2 346-351
92 Kopp E, Medzhitov R, Carothers J. et al . ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 1999; 13 2059-2071
93 Schroder N W, Pfeil D, Opitz B. et al . Activation of mitogen-activated protein kinases p42/44, p38, and stress-activated protein kinases in myelo-monocytic cells by Treponema lipoteichoic acid. J Biol Chem. 2001; 276 9713-9719
94 Navarro L, David M. p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. J Biol Chem. 1999; 274 35535-35538
95 Cario E, Mazurkiewicz J, Haar Dv.d. et al . Commensal-associated peptidoglycan activates distinct intestinal epithelial cell survival mechanisms via Toll-like receptor 2. Gastroenterology (Abstract-DDW2002). 2002; in press
96 Fitzgerald K A, Palsson-McDermott E M, Bowie A G. et al . Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature. 2001; 413 78-83
97 Kawai T, Takeuchi O, Fujita T. et al . Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol. 2001; 167 5887-5894
98 Byrd-Leifer C A, Block E F, Takeda K. et al . The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol. 2001; 31 2448-2457
99 Horng T, Barton G M, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol. 2001; 2 835-841
100 Dalpke A H, Opper S, Zimmermann S. et al . Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J Immunol. 2001; 166 7082-7089
101 Musikacharoen T, Matsuguchi T, Kikuchi T. et al . NF-kappa B and STAT5 play important roles in the regulation of mouse Toll-like receptor 2 gene expression. J Immunol. 2001; 166 4516-4524
102 Isberg R R, Normark S. Host microbe interactions: bacteria. Innate immune responses: attack and counter-attack. Curr Opin Microbiol. 2000; 3 13-15
103 Xavier R J, Podolsky D K. Microbiology. How to get along-friendly microbes in a hostile world [comment]. Science. 2000; 289 1483-1484
104 Neish A S, Gewirtz A T, Zeng H. et al . Prokaryotic regulation of epithelial responses by inhibition of IkappaB-alpha ubiquitination. Science. 2000; 289 1560-1563
105 Cario E, Podolsky D K. Lipopolysaccharide induces intestinal epithelial tolerance via downregulation of the Toll-like receptor (TLR) signaling pathway. Gastroenterology. 2001; 120 A-327 (abstract)
106 Otte J M, Cario E, Podolsky D K. Cross-tolerance of TLR ligands in intestinal epithelial cells. Gastroenterology (Abstract-DDW2002). 2002; in press
107 Lehner M D, Morath S, Michelsen K S. et al . Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different toll-like receptors independent of paracrine mediators. J Immunol. 2001; 166 5161-5167
108 Hajishengallis G, Martin M, Sojar H T. et al . Dependence of bacterial protein adhesins on toll-like receptors for proinflammatory cytokine induction. Clin Diagn Lab Immunol. 2002; 9 403-411
109 Medvedev A E, Kopydlowski K M, Vogel S N. Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and toll-like receptor 2 and 4 gene expression. J Immunol. 2000; 164 5564-5574
110 Sato S, Nomura F, Kawai T. et al . Synergy and cross-tolerance between toll-like receptor (TLR) 2- and TLR4-mediated signaling pathways. J Immunol. 2000; 165 7096-7101
111 Martin M, Katz J, Vogel S N. et al . Differential Induction of Endotoxin Tolerance by Lipopolysaccharides Derived from Porphyromonas gingivalis and Escherichia coli. J Immunol. 2001; 167 5278-5285
112 Levine A D. Apoptosis: implications for inflammatory bowel disease. Inflamm Bowel Dis. 2000; 6 191-206
113 Savill J. Phagocyte recognition of apoptotic cells. Biochem. Soc. Trans. 1996; 24 1065-1069
114 Anderson J M. Maintaining a defense as the injured leave the field: apoptosis and barrier function in the intestine. Gastroenterology. 2000; 119 1783-1787
115 Jones N L, Islur A, Haq R. et al . Escherichia coli Shiga toxins induce apoptosis in epithelial cells that is regulated by the Bcl-2 family. Am J Physiol Gastrointest Liver Physiol. 2000; 278 G811-819
116 Kim J M, Eckmann L, Savidge T C. et al . Apoptosis of human intestinal epithelial cells after bacterial invasion. J Clin Invest. 1998; 102 1815-1823
117 Wada Y, Mori K, Iwanaga T. Apoptosis of enterocytes induced by inoculation of a strain of attaching and effacing Escherichia coli and verotoxin. J Vet Med Sci. 1997; 59 815-818
118 Fish S M, Proujansky R, Reenstra W W. Synergistic effects of interferon gamma and tumour necrosis factor alpha on T84 cell function. Gut. 1999; 45 191-198
119 O'Connell J, Bennett M W, Nally K. et al . Interferon-gamma sensitizes colonic epithelial cell lines to physiological and therapeutic inducers of colonocyte apoptosis. J Cell Physiol. 2000; 185 331-338
120 Strater J, Walczak H, Wellisch I. et al . Normal colon epithelium is highly sensitive to CD95-induced apoptosis. Indications for a role of cell death-induced CD95/CD95L systems under inflammatory conditions. Verh Dtsch Ges Pathol. 1996; 80 217
121 Bu P, Keshavarzian A, Stone D D. et al . Apoptosis: one of the mechanisms that maintains unresponsiveness of the intestinal mucosal immune system. J. Immunol. 2001; 166 6399-6403
122 Abreu M T, Arnold E T, Chow J Y. et al . Phosphatidylinositol 3-kinase-dependent pathways oppose Fas-induced apoptosis and limit chloride secretion in human intestinal epithelial cells. Implications for inflammatory diarrheal states. J Biol Chem. 2001; 276 47563-47574
123 Öhd J F, Wikström K, Sjölander A. Leukotrienes induce cell-survival signaling in intestinal epithelial cells. Gastroenterology. 2000; 119 1007-1018
124 Gauthier R, Harnois C, Drolet J F. et al . Human intestinal epithelial cell survival: differentiation state-specific control mechanisms. Am J Physiol Cell Physiol. 2001; 280 C1540-1554
125 Choi K B, Wong F, Harlan J M. et al . Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway. J Biol Chem. 1998; 273 20185-20188
126 Monick M M, Carter A B, Robeff P K. et al . Lipopolysaccharide activates Akt in human alveolar macrophages resulting in nuclear accumulation and transcriptional activity of ß-catenin. J. Immunol. 2001; 166 4713-4720
127 Crouser E D, Julian M W, Weinstein D M. et al . Endotoxin-induced ileal mucosal injury and nitric oxide dysregulation are temporally dissociated. Am J Respir Crit Care Med. 2000; 161 1705-1712
128 Olaya J, Neopikhanov V, Uribe A. Lipopolysaccharide of Escherichia coli, polyamines, and acetic acid stimulate cell proliferation in intestinal epithelial cells. In Vitro Cell Dev Biol Anim. 1999; 35 43-48
129 Riehl T, Cohn S, Tessner T. et al . Lipopolysaccharide is radioprotective in the mouse intestine through a prostaglandin-mediated mechanism. Gastroenterology. 2000; 118 1106-1116
130 Aliprantis A O, Yang R B, Mark M R. et al . Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science. 1999; 285 736-739
131 Arbibe L, Mira J P, Teusch N. et al . Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol. 2000; 1 533-540
132 Roy S, Nicholson D W. Cross-talk in cell death signaling. J Exp Med. 2000; 192 F12-F25
133 Jaunin F, Burns K, Tschopp J. et al . Ultrastructural distribution of the death-domain-containing MyD88 protein in HeLa cells. Exp Cell Res. 1998; 243 67-75
134 Aliprantis A O, Yang R B, Weiss D S. et al . The apoptotic signaling pathway activated by Toll-like receptor-2. Embo J. 2000; 19 3325-3336
135 Dupraz P, Cottet S, Hamburger F. et al . Dominant negative MyD88 proteins inhibit interleukin-1beta /interferon-gamma mediated induction of nuclear factor kappa B-dependent nitrite production and apoptosis in beta cells. J Biol Chem. 2000; 275 37672-37678
136 Seki E, Tsutsui H, Nakano H. et al . Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of MyD88 that is critically involved in induction of production of IL-12 and IL-1β. J. Immunol. 2001; 166 2651-2657
137 Rokutan K, Kawahara T, Teshima S. et al . Regulation of cell growth and death of gastric mucosal cells by MOX1 and Toll-like receptors. Gastroenterology. 2000; 118 A539
138 Equils O, Faure E, Thomas L. et al . Bacterial lipopolysaccharide activates HIV long terminal repeat through Toll-like receptor 4. J. Immunol. 2001; 166 2342-2347
139 Inohara N, Koseki T, Lin J. et al . An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem. 2000; 275 27823-27831
140 Ogura Y, Inohara N, Benito A. et al . Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-kappa B. J Biol Chem. 2001; 276 4812-4818
141 Sansonetti P J, Van Tran N hieu G, Egile C. Rupture of the intestinal epithelial barrier and mucosal invasion by Shigella flexneri. Clin Infect Dis. 1999; 28 466-475
142 Podolsky D K. Inflammatory bowel disease (2). N Engl J Med. 1991; 325 1008-1016
143 Shanahan F. Inflammatory Bowel Disease: immunodiagnostics, immunotherapeutics, and ecotherapeutics. Gastroenterology. 2001; 120 622-635
144 Duchmann R, Kaiser I, Hermann E. et al . Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD) [see comments]. Clin Exp Immunol. 1995; 102 448-455
145 Caradonna L, Amati L, Magrone T. et al . Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J Endotoxin Res. 2000; 6 205-214
146 Sartor R B. Review article: Role of the enteric microflora in the pathogenesis of intestinal inflammation and arthritis. Aliment Pharmacol Ther. 1997; 11 Suppl 3 17-22; discussion 22 - 13
147 Podolsky D K. Lessons from genetic models of inflammatory bowel disease. Acta Gastroenterol Belg. 1997; 60 163-165
148 de Jong Y P, Abadia-Molina A C, Satoskar A R. et al . Development of chronic colitis is dependent on the cytokine MIF. Nat Immunol. 2001; 2 1061-1066
149 French N, Pettersson S. Microbe-host interactions in the alimentary tract: the gateway to understanding inflammatory bowel disease. Gut. 2000; 47 162-163

Dr. med. Elke Cario

Division of Gastroenterology & Hepatology, University of Essen, Institutsgruppe I / C / R. 8

Virchowstr. 171

45147 Essen

Email: elke.cario@uni-essen.de