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*
Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, and
Division of Pediatric Infectious Diseases, Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
The lumenal surface of the colonic epithelium is continually
exposed to Gram-negative commensal bacteria and LPS. Recognition of LPS
by Toll-like receptor (TLR)-4 results in proinflammatory gene
expression in diverse cell types. Normally, however, commensal bacteria
and their components do not elicit an inflammatory response from
intestinal epithelial cells (IEC). The aim of this study is to
understand the molecular mechanisms by which IEC limit chronic
activation in the presence of LPS. Three IEC lines (Caco-2, T84, HT-29)
were tested for their ability to activate an NF-
B reporter gene in
response to purified, protein-free LPS. No IEC line responded to LPS,
whereas human dermal microvessel endothelial cells (HMEC) did respond
to LPS. IEC responded vigorously to IL-1
in this assay,
demonstrating that the IL-1 receptor signaling pathway shared by TLRs
was intact. To determine the reason for LPS hyporesponsiveness in IEC,
we examined the expression of TLR4 and MD-2, a critical coreceptor for
TLR4 signaling. IEC expressed low levels of TLR4 compared with HMEC and
none expressed MD-2. To determine whether the low level of TLR4
expression or absent MD-2 was responsible for the LPS signaling defect
in IEC, the TLR4 or MD-2 gene was transiently expressed in IEC lines.
Transient transfection of either gene individually was not sufficient
to restore LPS signaling, but cotransfection of TLR4 and MD-2 in IEC
led to synergistic activation of NF-B and IL-8 reporter genes in
response to LPS. We conclude that IEC limit dysregulated LPS signaling
by down-regulating expression of MD-2 and TLR4. The remainder of the
intracellular LPS signaling pathway is functionally
intact.
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L. Armstrong, A. R. L. Medford, K. M. Uppington, J. Robertson, I. R. Witherden, T. D. Tetley, and A. B. Millar Expression of Functional Toll-Like Receptor-2 and -4 on Alveolar Epithelial Cells Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 241 - 245. [Abstract] [Full Text] [PDF]
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 H. P. Jia, J. N. Kline, A. Penisten, M. A. Apicella, T. L. Gioannini, J. Weiss, and P. B. McCray Jr. Endotoxin responsiveness of human airway epithelia is limited by low expression of MD-2 Am J Physiol Lung Cell Mol Physiol, August 1, 2004; 287(2): L428 - L437. [Abstract] [Full Text] [PDF]
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S. Ishihara, M. A. K. Rumi, Y. Kadowaki, C. F. Ortega-Cava, T. Yuki, N. Yoshino, Y. Miyaoka, H. Kazumori, N. Ishimura, Y. Amano, et al. Essential Role of MD-2 in TLR4-Dependent Signaling during Helicobacter pylori-Associated Gastritis J. Immunol., July 15, 2004; 173(2): 1406 - 1416. [Abstract] [Full Text] [PDF]
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D Franchimont, S Vermeire, H El Housni, M Pierik, K Van Steen, T Gustot, E Quertinmont, M Abramowicz, A Van Gossum, J Deviere, et al. Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn's disease and ulcerative colitis Gut, July 1, 2004; 53(7): 987 - 992. [Abstract] [Full Text] [PDF]
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S. Cetin, H. R. Ford, L. R. Sysko, C. Agarwal, J. Wang, M. D. Neal, C. Baty, G. Apodaca, and D. J. Hackam Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions J. Biol. Chem., June 4, 2004; 279(23): 24592 - 24600. [Abstract] [Full Text] [PDF]
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T. Guthrie, S. Y. C. Wong, B. Liang, L. Hyland, S. Hou, E. A. Hoiby, and S. R. Andersen Local and Systemic Antibody Responses in Mice Immunized Intranasally with Native and Detergent-Extracted Outer Membrane Vesicles from Neisseria meningitidis Infect. Immun., May 1, 2004; 72(5): 2528 - 2537. [Abstract] [Full Text] [PDF]
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K. Kojima, M. W. Musch, M. J. Ropeleski, D. L. Boone, A. Ma, and E. B. Chang Escherichia coli LPS induces heat shock protein 25 in intestinal epithelial cells through MAP kinase activation Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G645 - G652. [Abstract] [Full Text] [PDF]
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J. G. Kim, S. J. Lee, and M. F. Kagnoff Nod1 Is an Essential Signal Transducer in Intestinal Epithelial Cells Infected with Bacteria That Avoid Recognition by Toll-Like Receptors Infect. Immun., March 1, 2004; 72(3): 1487 - 1495. [Abstract] [Full Text] [PDF]
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T. Kawahara, Y. Kuwano, S. Teshima-Kondo, R. Takeya, H. Sumimoto, K. Kishi, S. Tsunawaki, T. Hirayama, and K. Rokutan Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 1 in Oxidative Burst Response to Toll-Like Receptor 5 Signaling in Large Intestinal Epithelial Cells J. Immunol., March 1, 2004; 172(5): 3051 - 3058. [Abstract] [Full Text] [PDF]
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M. M. Monick, T. O. Yarovinsky, L. S. Powers, N. S. Butler, A. B. Carter, G. Gudmundsson, and G. W. Hunninghake Respiratory Syncytial Virus Up-regulates TLR4 and Sensitizes Airway Epithelial Cells to Endotoxin J. Biol. Chem., December 26, 2003; 278(52): 53035 - 53044. [Abstract] [Full Text] [PDF]
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M. W. Hornef, B. H. Normark, A. Vandewalle, and S. Normark Intracellular Recognition of Lipopolysaccharide by Toll-like Receptor 4 in Intestinal Epithelial Cells J. Exp. Med., October 20, 2003; 198(8): 1225 - 1235. [Abstract] [Full Text] [PDF]
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 K. Peters, R. E. Unger, J. Brunner, and C.J. Kirkpatrick Molecular basis of endothelial dysfunction in sepsis Cardiovasc Res, October 15, 2003; 60(1): 49 - 57. [Abstract] [Full Text] [PDF]
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M. T. Abreu, L. S. Thomas, E. T. Arnold, K. Lukasek, K. S. Michelsen, and M. Arditi TLR signaling at the intestinal epithelial interface Innate Immunity, October 1, 2003; 9(5): 322 - 330. [Abstract] [PDF]
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T. Pedron, C. Thibault, and P. J. Sansonetti The Invasive Phenotype of Shigella flexneri Directs a Distinct Gene Expression Pattern in the Human Intestinal Epithelial Cell Line Caco-2 J. Biol. Chem., September 5, 2003; 278(36): 33878 - 33886. [Abstract] [Full Text] [PDF]
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M. Suzuki, T. Hisamatsu, and D. K. Podolsky Gamma Interferon Augments the Intracellular Pathway for Lipopolysaccharide (LPS) Recognition in Human Intestinal Epithelial Cells through Coordinated Up-Regulation of LPS Uptake and Expression of the Intracellular Toll-Like Receptor 4-MD-2 Complex Infect. Immun., June 1, 2003; 71(6): 3503 - 3511. [Abstract] [Full Text] [PDF]
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Y. Tsutsumi-Ishii and I. Nagaoka Modulation of Human {beta}-Defensin-2 Transcription in Pulmonary Epithelial Cells by Lipopolysaccharide-Stimulated Mononuclear Phagocytes Via Proinflammatory Cytokine Production J. Immunol., April 15, 2003; 170(8): 4226 - 4236. [Abstract] [Full Text] [PDF]
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M. D. Wheeler and R. G. Thurman Up-regulation of CD14 in Liver Caused by Acute Ethanol Involves Oxidant-dependent AP-1 Pathway J. Biol. Chem., February 28, 2003; 278(10): 8435 - 8441. [Abstract] [Full Text] [PDF]
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G. Melmed, L. S. Thomas, N. Lee, S. Y. Tesfay, K. Lukasek, K. S. Michelsen, Y. Zhou, B. Hu, M. Arditi, and M. T. Abreu Human Intestinal Epithelial Cells Are Broadly Unresponsive to Toll-Like Receptor 2-Dependent Bacterial Ligands: Implications for Host-Microbial Interactions in the Gut J. Immunol., February 1, 2003; 170(3): 1406 - 1415. [Abstract] [Full Text] [PDF]
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L. Liu, A. A. Roberts, and T. Ganz By IL-1 Signaling, Monocyte-Derived Cells Dramatically Enhance the Epidermal Antimicrobial Response to Lipopolysaccharide J. Immunol., January 1, 2003; 170(1): 575 - 580. [Abstract] [Full Text] [PDF]
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F M Ruemmele, J F Beaulieu, S Dionne, E Levy, E G Seidman, N Cerf-Bensussan, and M J Lentze Lipopolysaccharide modulation of normal enterocyte turnover by toll-like receptors is mediated by endogenously produced tumour necrosis factor {alpha} Gut, December 1, 2002; 51(6): 842 - 848. [Abstract] [Full Text] [PDF]
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D. Haller, M. P. Russo, R. B. Sartor, and C. Jobin IKKbeta and Phosphatidylinositol 3-Kinase/Akt Participate in Non-pathogenic Gram-negative Enteric Bacteria-induced RelA Phosphorylation and NF-kappa B Activation in Both Primary and Intestinal Epithelial Cell Lines J. Biol. Chem., October 4, 2002; 277(41): 38168 - 38178. [Abstract] [Full Text] [PDF]
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R. M. Hershberg The Epithelial Cell Cytoskeleton and Intracellular Trafficking: V. Polarized compartmentalization of antigen processing and Toll-like receptor signaling in intestinal epithelial cells Am J Physiol Gastrointest Liver Physiol, October 1, 2002; 283(4): G833 - G839. [Abstract] [Full Text] [PDF]
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P. Henneke, O. Takeuchi, R. Malley, E. Lien, R. R. Ingalls, M. W. Freeman, T. Mayadas, V. Nizet, S. Akira, D. L. Kasper, et al. Cellular Activation, Phagocytosis, and Bactericidal Activity Against Group B Streptococcus Involve Parallel Myeloid Differentiation Factor 88-Dependent and Independent Signaling Pathways J. Immunol., October 1, 2002; 169(7): 3970 - 3977. [Abstract] [Full Text] [PDF]
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Z. H. Nemeth, E. A. Deitch, C. Szabo, and G. Hasko Hyperosmotic Stress Induces Nuclear Factor-{kappa}B Activation and Interleukin-8 Production in Human Intestinal Epithelial Cells Am. J. Pathol., September 1, 2002; 161(3): 987 - 996. [Abstract] [Full Text] [PDF]
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J. Fierer, M. A. Swancutt, D. Heumann, and D. Golenbock The Role of Lipopolysaccharide Binding Protein in Resistance to Salmonella Infections in Mice J. Immunol., June 15, 2002; 168(12): 6396 - 6403. [Abstract] [Full Text] [PDF]
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M. T. Abreu, E. T. Arnold, L. S. Thomas, R. Gonsky, Y. Zhou, B. Hu, and M. Arditi TLR4 and MD-2 Expression Is Regulated by Immune-mediated Signals in Human Intestinal Epithelial Cells J. Biol. Chem., May 31, 2002; 277(23): 20431 - 20437. [Abstract] [Full Text] [PDF]
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Z. H. Nemeth, E. A. Deitch, C. Szabo, Z. Fekete, C. J. Hauser, and G. Hasko Lithium Induces NF-kappa B Activation and Interleukin-8 Production in Human Intestinal Epithelial Cells J. Biol. Chem., March 1, 2002; 277(10): 7713 - 7719. [Abstract] [Full Text] [PDF]
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R. N. Fichorova, A. O. Cronin, E. Lien, D. J. Anderson, and R. R. Ingalls Response to Neisseria gonorrhoeae by Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling J. Immunol., March 1, 2002; 168(5): 2424 - 2432. [Abstract] [Full Text] [PDF]
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M. W. Hornef, T. Frisan, A. Vandewalle, S. Normark, and A. Richter-Dahlfors Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells J. Exp. Med., February 25, 2002; 195(5): 559 - 570. [Abstract] [Full Text] [PDF]
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 C. Li, Y. Wang, L. Gao, J. Zhang, J. Shao, S. Wang, W. Feng, X. Wang, M. Li, and Z. Chang Expression of Toll-like Receptors 2 and 4 and CD14 during Differentiation of HL-60 Cells Induced by Phorbol 12-Myristate 13-Acetate and 1{alpha}, 25-Dihydroxy-Vitamin D3 Cell Growth Differ., January 1, 2002; 13(1): 27 - 38. [Abstract] [Full Text] [PDF]
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E. Cario, D. Brown, M. McKee, K. Lynch-Devaney, G. Gerken, and D. K. Podolsky Commensal-Associated Molecular Patterns Induce Selective Toll-Like Receptor-Trafficking from Apical Membrane to Cytoplasmic Compartments in Polarized Intestinal Epithelium Am. J. Pathol., January 1, 2002; 160(1): 165 - 173. [Abstract] [Full Text] [PDF]
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