Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 493K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hornef, M. W. Articles by Richter-Dahlfors, A. Search for Related Content PubMed PubMed Citation Articles by Hornef, M. W. Articles by Richter-Dahlfors, A. Social Bookmarking                            What's this?

Original Article

¹ Microbiology and Tumor Biology Center, Karolinska Institutet, 17177 Stockholm, Sweden
² Institut National de la Santé et de la Recherche Médicale (INSERM) U478, Faculté de Médecine Xavier Bichat, 75018 Paris Cedex 18, France

Address correspondence to Mathias Hornef, Microbiology and Tumor Biology Center, Karolinska Institutet, Theorellsväg 3, 17177-Stockholm, Sweden. Phone: 46-8-7287409; Fax: 46-8-342651; E-mail: mathias.hornef{at}mtc.ki.se

Toll-like receptor (TLR) 4 is mainly found on cells of the myelopoietic lineage. It recognizes lipopolysaccharide (LPS) and mediates cellular activation and production of proinflammatory cytokines. Less is known about the distribution and role of TLR4 in epithelial cells that are continuously exposed to microbes and microbial products. Here we show that the murine small intestinal epithelial cell line m-IC_cl2 is highly responsive to LPS and expresses both CD14 and TLR4. Transcription and surface membrane staining for CD14 were up-regulated upon LPS exposure. Surprisingly, TLR4 immunostaining revealed a strictly cytoplasmic paranuclear distribution. This paranuclear compartment could be identified as the Golgi apparatus. LPS added to the supernatant was internalized by m-IC_cl2 cells and colocalized with TLR4. Continuous exposure to LPS led to a tolerant phenotype but did not alter TLR4 expression nor cellular distribution. Thus, intestinal epithelial cells might be able to provide the initial proinflammatory signal to attract professional immune cells to the side of infection. The cytoplasmic location of TLR4, which is identical to the final location of internalized LPS, further indicates an important role of cellular internalization and cytoplasmic traffic in the process of innate immune recognition.

Key Words: toll-like receptor 4 • Golgi apparatus • lipopolysaccharide • CD14 • LPS tolerance

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Louis, N. A., Lin, P. W. (2009). The Intestinal Immune Barrier. NeoReviews 10: e180-e190 [Abstract] [Full Text]  
• Wu, M., McClellan, S. A., Barrett, R. P., Hazlett, L. D. (2009). {beta}-Defensin-2 Promotes Resistance against Infection with P. aeruginosa. J. Immunol. 182: 1609-1616 [Abstract] [Full Text]  
• Ghoshal, S., Witta, J., Zhong, J., de Villiers, W., Eckhardt, E. (2009). Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50: 90-97 [Abstract] [Full Text]  
• Gribar, S. C., Sodhi, C. P., Richardson, W. M., Anand, R. J., Gittes, G. K., Branca, M. F., Jakub, A., Shi, X.-h., Shah, S., Ozolek, J. A., Hackam, D. J. (2009). Reciprocal Expression and Signaling of TLR4 and TLR9 in the Pathogenesis and Treatment of Necrotizing Enterocolitis. J. Immunol. 182: 636-646 [Abstract] [Full Text]  
• Vaishnava, S., Behrendt, C. L., Ismail, A. S., Eckmann, L., Hooper, L. V. (2008). Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc. Natl. Acad. Sci. USA 105: 20858-20863 [Abstract] [Full Text]  
• Bhattacharyya, S., Dudeja, P. K., Tobacman, J. K. (2008). Lipopolysaccharide activates NF-{kappa}B by TLR4-Bcl10-dependent and independent pathways in colonic epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 295: G784-G790 [Abstract] [Full Text]  
• El-Achkar, T. M., Wu, X.-R., Rauchman, M., McCracken, R., Kiefer, S., Dagher, P. C. (2008). Tamm-Horsfall protein protects the kidney from ischemic injury by decreasing inflammation and altering TLR4 expression. Am. J. Physiol. Renal Physiol. 295: F534-F544 [Abstract] [Full Text]  
• Meyer-Hoffert, U, Hornef, M W, Henriques-Normark, B, Axelsson, L-G, Midtvedt, T, Putsep, K, Andersson, M (2008). Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut 57: 764-771 [Abstract] [Full Text]  
• Chang, S. K., Mihalcik, S. A., Jelinek, D. F. (2008). B Lymphocyte Stimulator Regulates Adaptive Immune Responses by Directly Promoting Dendritic Cell Maturation. J. Immunol. 180: 7394-7403 [Abstract] [Full Text]  
• Gong, P., Angelini, D. J., Yang, S., Xia, G., Cross, A. S., Mann, D., Bannerman, D. D., Vogel, S. N., Goldblum, S. E. (2008). TLR4 Signaling Is Coupled to SRC Family Kinase Activation, Tyrosine Phosphorylation of Zonula Adherens Proteins, and Opening of the Paracellular Pathway in Human Lung Microvascular Endothelia. J. Biol. Chem. 283: 13437-13449 [Abstract] [Full Text]  
• Bhattacharyya, S., Gill, R., Chen, M. L., Zhang, F., Linhardt, R. J., Dudeja, P. K., Tobacman, J. K. (2008). Toll-like Receptor 4 Mediates Induction of the Bcl10-NF{kappa}B-Interleukin-8 Inflammatory Pathway by Carrageenan in Human Intestinal Epithelial Cells. J. Biol. Chem. 283: 10550-10558 [Abstract] [Full Text]  
• Gribar, S. C., Anand, R. J., Sodhi, C. P., Hackam, D. J. (2008). The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J. Leukoc. Biol. 83: 493-498 [Abstract] [Full Text]  
• Davey, M., Liu, X., Ukai, T., Jain, V., Gudino, C., Gibson, F. C. III, Golenbock, D., Visintin, A., Genco, C. A. (2008). Bacterial Fimbriae Stimulate Proinflammatory Activation in the Endothelium through Distinct TLRs. J. Immunol. 180: 2187-2195 [Abstract] [Full Text]  
• Tissieres, P., Dunn-Siegrist, I., Schappi, M., Elson, G., Comte, R., Nobre, V., Pugin, J. (2008). Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria. Blood 111: 2122-2131 [Abstract] [Full Text]  
• Chassin, C., Hornef, M. W., Bens, M., Lotz, M., Goujon, J.-M., Vimont, S., Arlet, G., Hertig, A., Rondeau, E., Vandewalle, A. (2007). Hormonal control of the renal immune response and antibacterial host defense by arginine vasopressin. JEM 204: 2837-2852 [Abstract] [Full Text]  
• Andreani, V., Gatti, G., Simonella, L., Rivero, V., Maccioni, M. (2007). Activation of Toll-like Receptor 4 on Tumor Cells In vitro Inhibits Subsequent Tumor Growth In vivo. Cancer Res. 67: 10519-10527 [Abstract] [Full Text]  
• Shuang Chen, , Wong, M. H., Schulte, D. J., Arditi, M., Michelsen, K. S. (2007). Differential expression of Toll-like receptor 2 (TLR2) and responses to TLR2 ligands between human and murine vascular endothelial cells. Innate Immunity 13: 281-296 [Abstract]  
• Lichtinger, M., Ingram, R., Hornef, M., Bonifer, C., Rehli, M. (2007). Transcription Factor PU.1 Controls Transcription Start Site Positioning and Alternative TLR4 Promoter Usage. J. Biol. Chem. 282: 26874-26883 [Abstract] [Full Text]  
• Bogunovic, M., Dave, S. H., Tilstra, J. S., Chang, D. T. W., Harpaz, N., Xiong, H., Mayer, L. F., Plevy, S. E. (2007). Enteroendocrine cells express functional Toll-like receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 292: G1770-G1783 [Abstract] [Full Text]  
• Karrasch, T., Kim, J.-S., Muhlbauer, M., Magness, S. T., Jobin, C. (2007). Gnotobiotic IL-10-/-;NF-{kappa}BEGFP Mice Reveal the Critical Role of TLR/NF-{kappa}B Signaling in Commensal Bacteria-Induced Colitis. J. Immunol. 178: 6522-6532 [Abstract] [Full Text]  
• Mayer, A. K., Muehmer, M., Mages, J., Gueinzius, K., Hess, C., Heeg, K., Bals, R., Lang, R., Dalpke, A. H. (2007). Differential Recognition of TLR-Dependent Microbial Ligands in Human Bronchial Epithelial Cells. J. Immunol. 178: 3134-3142 [Abstract] [Full Text]  
• Sun, J., Fegan, P. E., Desai, A. S., Madara, J. L., Hobert, M. E. (2007). Flagellin-induced tolerance of the Toll-like receptor 5 signaling pathway in polarized intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol. 292: G767-G778 [Abstract] [Full Text]  
• Quintar, A. A., Roth, F. D., Paul, A. L. D., Aoki, A., Maldonado, C. A. (2006). Toll-Like Receptor 4 in Rat Prostate: Modulation by Testosterone and Acute Bacterial Infection in Epithelial and Stromal Cells. Biol. Reprod. 75: 664-672 [Abstract] [Full Text]  
• Chassin, C., Goujon, J.-M., Darche, S., du Merle, L., Bens, M., Cluzeaud, F., Werts, C., Ogier-Denis, E., Le Bouguenec, C., Buzoni-Gatel, D., Vandewalle, A. (2006). Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways. J. Immunol. 177: 4773-4784 [Abstract] [Full Text]  
• Miyake, K. (2006). Invited review: Roles for accessory molecules in microbial recognition by Toll-like receptors. Innate Immunity 12: 195-204 [Abstract]  
• Gatti, G., Rivero, V., Motrich, R. D., Maccioni, M. (2006). Prostate epithelial cells can act as early sensors of infection by up-regulating TLR4 expression and proinflammatory mediators upon LPS stimulation. J. Leukoc. Biol. 79: 989-998 [Abstract] [Full Text]  
• El-Achkar, T. M., Huang, X., Plotkin, Z., Sandoval, R. M., Rhodes, G. J., Dagher, P. C. (2006). Sepsis induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am. J. Physiol. Renal Physiol. 290: F1034-F1043 [Abstract] [Full Text]  
• Lotz, M., Gutle, D., Walther, S., Menard, S., Bogdan, C., Hornef, M. W. (2006). Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. JEM 203: 973-984 [Abstract] [Full Text]  
• Yu, F.-S. X., Hazlett, L. D. (2006). Toll-like Receptors and the Eye.. IOVS 47: 1255-1263 [Full Text]  
• Chabot, S., Wagner, J. S., Farrant, S., Neutra, M. R. (2006). TLRs Regulate the Gatekeeping Functions of the Intestinal Follicle-Associated Epithelium. J. Immunol. 176: 4275-4283 [Abstract] [Full Text]  
• Neal, M. D., Leaphart, C., Levy, R., Prince, J., Billiar, T. R., Watkins, S., Li, J., Cetin, S., Ford, H., Schreiber, A., Hackam, D. J. (2006). Enterocyte TLR4 Mediates Phagocytosis and Translocation of Bacteria Across the Intestinal Barrier.. J. Immunol. 176: 3070-3079 [Abstract] [Full Text]  
• Ismail, A. S., Hooper, L. V. (2005). Epithelial Cells and Their Neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity. Am. J. Physiol. Gastrointest. Liver Physiol. 289: G779-G784 [Abstract] [Full Text]  
• Maung, A. A., Fujimi, S., Miller, M. L., MacConmara, M. P., Mannick, J. A., Lederer, J. A. (2005). Enhanced TLR4 reactivity following injury is mediated by increased p38 activation. J. Leukoc. Biol. 78: 565-573 [Abstract] [Full Text]  
• Cario, E (2005). BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2. Gut 54: 1182-1193 [Full Text]  
• Fazeli, A., Bruce, C., Anumba, D.O. (2005). Characterization of Toll-like receptors in the female reproductive tract in humans. Hum Reprod 20: 1372-1378 [Abstract] [Full Text]  
• Abreu, M. T., Fukata, M., Arditi, M. (2005). TLR Signaling in the Gut in Health and Disease. J. Immunol. 174: 4453-4460 [Abstract] [Full Text]  
• Suzuki, T., Nakanishi, K., Tsutsui, H., Iwai, H., Akira, S., Inohara, N., Chamaillard, M., Nunez, G., Sasakawa, C. (2005). A Novel Caspase-1/Toll-like Receptor 4-independent Pathway of Cell Death Induced by Cytosolic Shigella in Infected Macrophages. J. Biol. Chem. 280: 14042-14050 [Abstract] [Full Text]  
• Hornef, M. W., Bogdan, C. (2005). The role of epithelial Toll-like receptor expression in host defense and microbial tolerance. Innate Immunity 11: 124-128 [Abstract]  
• Ruiz, P. A., Shkoda, A., Kim, S. C., Sartor, R. B., Haller, D. (2005). IL-10 Gene-Deficient Mice Lack TGF-{beta}/Smad Signaling and Fail to Inhibit Proinflammatory Gene Expression in Intestinal Epithelial Cells after the Colonization with Colitogenic Enterococcus faecalis. J. Immunol. 174: 2990-2999 [Abstract] [Full Text]  
• Hapfelmeier, S., Stecher, B., Barthel, M., Kremer, M., Muller, A. J., Heikenwalder, M., Stallmach, T., Hensel, M., Pfeffer, K., Akira, S., Hardt, W.-D. (2005). The Salmonella Pathogenicity Island (SPI)-2 and SPI-1 Type III Secretion Systems Allow Salmonella Serovar typhimurium to Trigger Colitis via MyD88-Dependent and MyD88-Independent Mechanisms. J. Immunol. 174: 1675-1685 [Abstract] [Full Text]  
• Bambou, J.-C., Giraud, A., Menard, S., Begue, B., Rakotobe, S., Heyman, M., Taddei, F., Cerf-Bensussan, N., Gaboriau-Routhiau, V. (2004). In Vitro and ex Vivo Activation of the TLR5 Signaling Pathway in Intestinal Epithelial Cells by a Commensal Escherichia coli Strain. J. Biol. Chem. 279: 42984-42992 [Abstract] [Full Text]  
• Triantafilou, M., Manukyan, M., Mackie, A., Morath, S., Hartung, T., Heine, H., Triantafilou, K. (2004). Lipoteichoic Acid and Toll-like Receptor 2 Internalization and Targeting to the Golgi Are Lipid Raft-dependent. J. Biol. Chem. 279: 40882-40889 [Abstract] [Full Text]  
• Ueta, M., Nochi, T., Jang, M.-H., Park, E. J., Igarashi, O., Hino, A., Kawasaki, S., Shikina, T., Hiroi, T., Kinoshita, S., Kiyono, H. (2004). Intracellularly Expressed TLR2s and TLR4s Contribution to an Immunosilent Environment at the Ocular Mucosal Epithelium. J. Immunol. 173: 3337-3347 [Abstract] [Full Text]  
• Bocharov, A. V., Baranova, I. N., Vishnyakova, T. G., Remaley, A. T., Csako, G., Thomas, F., Patterson, A. P., Eggerman, T. L. (2004). Targeting of Scavenger Receptor Class B Type I by Synthetic Amphipathic {alpha}-Helical-containing Peptides Blocks Lipopolysaccharide (LPS) Uptake and LPS-induced Pro-inflammatory Cytokine Responses in THP-1 Monocyte Cells. J. Biol. Chem. 279: 36072-36082 [Abstract] [Full Text]  
• Funami, K., Matsumoto, M., Oshiumi, H., Akazawa, T., Yamamoto, A., Seya, T. (2004). The cytoplasmic 'linker region' in Toll-like receptor 3 controls receptor localization and signaling. Int Immunol 16: 1143-1154 [Abstract] [Full Text]  
• Kindzelskii, A. L., Elner, V. M., Elner, S. G., Yang, D., Hughes, B. A., Petty, H. R. (2004). Toll-Like Receptor 4 (TLR4) of Retinal Pigment Epithelial Cells Participates in Transmembrane Signaling in Response to Photoreceptor Outer Segments. JGP 124: 139-149 [Abstract] [Full Text]  
• Leifer, C. A., Kennedy, M. N., Mazzoni, A., Lee, C., Kruhlak, M. J., Segal, D. M. (2004). TLR9 Is Localized in the Endoplasmic Reticulum Prior to Stimulation. J. Immunol. 173: 1179-1183 [Abstract] [Full Text]  
• Cetin, S., Ford, H. R., Sysko, L. R., Agarwal, C., Wang, J., Neal, M. D., Baty, C., Apodaca, G., Hackam, D. J. (2004). Endotoxin Inhibits Intestinal Epithelial Restitution through Activation of Rho-GTPase and Increased Focal Adhesions. J. Biol. Chem. 279: 24592-24600 [Abstract] [Full Text]  
• Nishiya, T., DeFranco, A. L. (2004). Ligand-regulated Chimeric Receptor Approach Reveals Distinctive Subcellular Localization and Signaling Properties of the Toll-like Receptors. J. Biol. Chem. 279: 19008-19017 [Abstract] [Full Text]  
• Guillot, L., Medjane, S., Le-Barillec, K., Balloy, V., Danel, C., Chignard, M., Si-Tahar, M. (2004). Response of Human Pulmonary Epithelial Cells to Lipopolysaccharide Involves Toll-like Receptor 4 (TLR4)-dependent Signaling Pathways: EVIDENCE FOR AN INTRACELLULAR COMPARTMENTALIZATION OF TLR4. J. Biol. Chem. 279: 2712-2718 [Abstract] [Full Text]  
• Imler, J.-L., Zheng, L. (2004). Biology of Toll receptors: lessons from insects and mammals. J. Leukoc. Biol. 75: 18-26 [Abstract] [Full Text]  
• Lee, J.-H., Del Sorbo, L., Uhlig, S., Porro, G. A., Whitehead, T., Voglis, S., Liu, M., Slutsky, A. S., Zhang, H. (2004). Intercellular Adhesion Molecule-1 Mediates Cellular Cross-Talk between Parenchymal and Immune Cells after Lipopolysaccharide Neutralization. J. Immunol. 172: 608-616 [Abstract] [Full Text]  
• Latz, E., Visintin, A., Lien, E., Fitzgerald, K. A., Espevik, T., Golenbock, D. T. (2003). The LPS receptor generates inflammatory signals from the cell surface. Innate Immunity 9: 375-380 [Abstract]  
• Frleta, D., Noelle, R. J., Wade, W. F. (2003). CD40-mediated up-regulation of Toll-like receptor 4-MD2 complex on the surface of murine dendritic cells. J. Leukoc. Biol. 74: 1064-1073 [Abstract] [Full Text]  
• Kalupahana, R., Emilianus, A. R., Maskell, D., Blacklaws, B. (2003). Salmonella enterica Serovar Typhimurium Expressing Mutant Lipid A with Decreased Endotoxicity Causes Maturation of Murine Dendritic Cells. Infect. Immun. 71: 6132-6140 [Abstract] [Full Text]  
• Hornef, M. W., Normark, B. H., Vandewalle, A., Normark, S. (2003). Intracellular Recognition of Lipopolysaccharide by Toll-like Receptor 4 in Intestinal Epithelial Cells. JEM 198: 1225-1235 [Abstract] [Full Text]  
• Zeng, H., Carlson, A. Q., Guo, Y., Yu, Y., Collier-Hyams, L. S., Madara, J. L., Gewirtz, A. T., Neish, A. S. (2003). Flagellin Is the Major Proinflammatory Determinant of Enteropathogenic Salmonella. J. Immunol. 171: 3668-3674 [Abstract] [Full Text]  
• Uehori, J., Matsumoto, M., Tsuji, S., Akazawa, T., Takeuchi, O., Akira, S., Kawata, T., Azuma, I., Toyoshima, K., Seya, T. (2003). Simultaneous Blocking of Human Toll-Like Receptors 2 and 4 Suppresses Myeloid Dendritic Cell Activation Induced by Mycobacterium bovis Bacillus Calmette-Guerin Peptidoglycan. Infect. Immun. 71: 4238-4249 [Abstract] [Full Text]  
• Bihl, F., Salez, L., Beaubier, M., Torres, D., Lariviere, L., Laroche, L., Benedetto, A., Martel, D., Lapointe, J.-M., Ryffel, B., Malo, D. (2003). Overexpression of Toll-Like Receptor 4 Amplifies the Host Response to Lipopolysaccharide and Provides a Survival Advantage in Transgenic Mice. J. Immunol. 170: 6141-6150 [Abstract] [Full Text]  
• Suzuki, M., Hisamatsu, T., Podolsky, D. K. (2003). 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. 71: 3503-3511 [Abstract] [Full Text]  
• Ortega-Cava, C. F., Ishihara, S., Rumi, M. A. K., Kawashima, K., Ishimura, N., Kazumori, H., Udagawa, J., Kadowaki, Y., Kinoshita, Y. (2003). Strategic Compartmentalization of Toll-Like Receptor 4 in the Mouse Gut. J. Immunol. 170: 3977-3985 [Abstract] [Full Text]  
• Liu, L., Roberts, A. A., Ganz, T. (2003). By IL-1 Signaling, Monocyte-Derived Cells Dramatically Enhance the Epidermal Antimicrobial Response to Lipopolysaccharide. J. Immunol. 170: 575-580 [Abstract] [Full Text]  
• Latz, E., Visintin, A., Lien, E., Fitzgerald, K. A., Monks, B. G., Kurt-Jones, E. A., Golenbock, D. T., Espevik, T. (2002). Lipopolysaccharide Rapidly Traffics to and from the Golgi Apparatus with the Toll-like Receptor 4-MD-2-CD14 Complex in a Process That Is Distinct from the Initiation of Signal Transduction. J. Biol. Chem. 277: 47834-47843 [Abstract] [Full Text]  
• Biragyn, A., Ruffini, P. A., Leifer, C. A., Klyushnenkova, E., Shakhov, A., Chertov, O., Shirakawa, A. K., Farber, J. M., Segal, D. M., Oppenheim, J. J., Kwak, L. W. (2002). Toll-Like Receptor 4-Dependent Activation of Dendritic Cells by beta -Defensin 2. Science 298: 1025-1029 [Abstract] [Full Text]  
• Medvedev, A. E., Lentschat, A., Wahl, L. M., Golenbock, D. T., Vogel, S. N. (2002). Dysregulation of LPS-Induced Toll-Like Receptor 4-MyD88 Complex Formation and IL-1 Receptor-Associated Kinase 1 Activation in Endotoxin-Tolerant Cells. J. Immunol. 169: 5209-5216 [Abstract] [Full Text]  
• Hershberg, R. M. (2002). 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. 283: G833-G839 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS