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*Substance via MeSH
The Journal of Immunology, 2001, 167: 1882-1885.
Copyright © 2001 by The American Association of Immunologists


Cutting Edge

Cutting Edge: Bacterial Flagellin Activates Basolaterally Expressed TLR5 to Induce Epithelial Proinflammatory Gene Expression1

Andrew T. Gewirtz2,3,*, Tony A. Navas3,{dagger}, Sean Lyons*, Paul J. Godowski2,{dagger} and James L. Madara*

* Epithelial Pathobiology Division, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; and {dagger} Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080

Flagellin, the structural component of bacterial flagella, is secreted by pathogenic and commensal bacteria. Flagellin activates proinflammatory gene expression in intestinal epithelia. However, only flagellin that contacts basolateral epithelial surfaces is proinflammatory; apical flagellin has no effect. Pathogenic Salmonella, but not commensal Escherichia coli, translocate flagellin across epithelia, thus activating epithelial proinflammatory gene expression. Investigating how epithelia detect flagellin revealed that cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-{kappa}B gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88. Furthermore, immunolocalization and cell surface-selective biotinylation revealed that TLR5 is expressed exclusively on the basolateral surface of intestinal epithelia, thus providing a molecular basis for the polarity of this innate immune response. Thus, detection of flagellin by basolateral TLR5 mediates epithelial-driven inflammatory responses to Salmonella.




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J. Immunol.Home page
J. Chun and A. Prince
Activation of Ca2+-Dependent Signaling by TLR2
J. Immunol., July 15, 2006; 177(2): 1330 - 1337.
[Abstract] [Full Text] [PDF]


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Infect. Immun.Home page
P. A. Johanesen and M. B. Dwinell
Flagellin-Independent Regulation of Chemokine Host Defense in Campylobacter jejuni-Infected Intestinal Epithelium.
Infect. Immun., June 1, 2006; 74(6): 3437 - 3447.
[Abstract] [Full Text] [PDF]


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Arch SurgHome page
L. Romics Jr, G. Szabo, J. C. Coffey, J. H. Wang, and H. P. Redmond
The Emerging Role of Toll-Like Receptor Pathways in Surgical Diseases
Arch Surg, June 1, 2006; 141(6): 595 - 601.
[Abstract] [Full Text] [PDF]


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Am. J. Respir. Cell Mol. Bio.Home page
N. McNamara, M. Gallup, A. Sucher, I. Maltseva, D. McKemy, and C. Basbaum
AsialoGM1 and TLR5 Cooperate in Flagellin-Induced Nucleotide Signaling to Activate Erk1/2
Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 653 - 660.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. T. Gewirtz, M. Vijay-Kumar, S. R. Brant, R. H. Duerr, D. L. Nicolae, and J. H. Cho
Dominant-negative TLR5 polymorphism reduces adaptive immune response to flagellin and negatively associates with Crohn's disease
Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1157 - G1163.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
Y. Yu, S. Nagai, H. Wu, A. S. Neish, S. Koyasu, and A. T. Gewirtz
TLR5-Mediated Phosphoinositide 3-Kinase Activation Negatively Regulates Flagellin-Induced Proinflammatory Gene Expression
J. Immunol., May 15, 2006; 176(10): 6194 - 6201.
[Abstract] [Full Text] [PDF]


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Am. J. Respir. Cell Mol. Bio.Home page
A. Prince
Flagellar Activation of Epithelial Signaling
Am. J. Respir. Cell Mol. Biol., May 1, 2006; 34(5): 548 - 551.
[Abstract] [Full Text] [PDF]


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Clin. Microbiol. Rev.Home page
V. Lievin-Le Moal and A. L. Servin
The Front Line of Enteric Host Defense against Unwelcome Intrusion of Harmful Microorganisms: Mucins, Antimicrobial Peptides, and Microbiota
Clin. Microbiol. Rev., April 1, 2006; 19(2): 315 - 337.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
W. Lu, A. Hisatsune, T. Koga, K. Kato, I. Kuwahara, E. P. Lillehoj, W. Chen, A. S. Cross, S. J. Gendler, A. T. Gewirtz, et al.
Cutting Edge: Enhanced Pulmonary Clearance of Pseudomonas aeruginosa by Muc1 Knockout Mice
J. Immunol., April 1, 2006; 176(7): 3890 - 3894.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
S. Chabot, J. S. Wagner, S. Farrant, and M. R. Neutra
TLRs Regulate the Gatekeeping Functions of the Intestinal Follicle-Associated Epithelium
J. Immunol., April 1, 2006; 176(7): 4275 - 4283.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
R. Sharma, S. Tesfay, F. L. Tomson, R. P. Kanteti, V. K. Viswanathan, and G. Hecht
Balance of bacterial pro- and anti-inflammatory mediators dictates net effect of enteropathogenic Escherichia coli on intestinal epithelial cells
Am J Physiol Gastrointest Liver Physiol, April 1, 2006; 290(4): G685 - G694.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Cell Physiol.Home page
J. Tseng, J. Do, J. H. Widdicombe, and T. E. Machen
Innate immune responses of human tracheal epithelium to Pseudomonas aeruginosa flagellin, TNF-{alpha}, and IL-1beta
Am J Physiol Cell Physiol, March 1, 2006; 290(3): C678 - C690.
[Abstract] [Full Text] [PDF]


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GutHome page
C Mueller and A J Macpherson
Layers of mutualism with commensal bacteria protect us from intestinal inflammation
Gut, February 1, 2006; 55(2): 276 - 284.
[Full Text] [PDF]


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Infect. Immun.Home page
M. Raffatellu, D. Chessa, R. P. Wilson, C. Tukel, M. Akcelik, and A. J. Baumler
Capsule-Mediated Immune Evasion: a New Hypothesis Explaining Aspects of Typhoid Fever Pathogenesis
Infect. Immun., January 1, 2006; 74(1): 19 - 27.
[Full Text] [PDF]


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CVIHome page
C. F. Ortega-Cava, S. Ishihara, M. A. K. Rumi, M. M. Aziz, H. Kazumori, T. Yuki, Y. Mishima, I. Moriyama, C. Kadota, N. Oshima, et al.
Epithelial Toll-Like Receptor 5 Is Constitutively Localized in the Mouse Cecum and Exhibits Distinctive Down-Regulation during Experimental Colitis
Clin. Vaccine Immunol., January 1, 2006; 13(1): 132 - 138.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
H. Zeng, H. Wu, V. Sloane, R. Jones, Y. Yu, P. Lin, A. T. Gewirtz, and A. S. Neish
Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways
Am J Physiol Gastrointest Liver Physiol, January 1, 2006; 290(1): G96 - G108.
[Abstract] [Full Text] [PDF]


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Infect. Immun.Home page
A. Verma, S. K. Arora, S. K. Kuravi, and R. Ramphal
Roles of Specific Amino Acids in the N Terminus of Pseudomonas aeruginosa Flagellin and of Flagellin Glycosylation in the Innate Immune Response
Infect. Immun., December 1, 2005; 73(12): 8237 - 8246.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
X.-M. Chen, S. P. O'Hara, J. B. Nelson, P. L. Splinter, A. J. Small, P. S. Tietz, A. H. Limper, and N. F. LaRusso
Multiple TLRs Are Expressed in Human Cholangiocytes and Mediate Host Epithelial Defense Responses to Cryptosporidium parvum via Activation of NF-{kappa}B
J. Immunol., December 1, 2005; 175(11): 7447 - 7456.
[Abstract] [Full Text] [PDF]


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Infect. Immun.Home page
Z. Zhang, J.-P. Louboutin, D. J. Weiner, J. B. Goldberg, and J. M. Wilson
Human Airway Epithelial Cells Sense Pseudomonas aeruginosa Infection via Recognition of Flagellin by Toll-Like Receptor 5
Infect. Immun., November 1, 2005; 73(11): 7151 - 7160.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. S. Ismail and L. V. Hooper
Epithelial Cells and Their Neighbors. IV. Bacterial contributions to intestinal epithelial barrier integrity
Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G779 - G784.
[Abstract] [Full Text] [PDF]


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Infect. Immun.Home page
R. W. DePaolo, R. Lathan, B. J. Rollins, and W. J. Karpus
The Chemokine CCL2 Is Required for Control of Murine Gastric Salmonella enterica Infection
Infect. Immun., October 1, 2005; 73(10): 6514 - 6522.
[Abstract] [Full Text] [PDF]


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Infect. Immun.Home page
O. Pino, M. Martin, and S. M. Michalek
Cellular Mechanisms of the Adjuvant Activity of the Flagellin Component FljB of Salmonella enterica Serovar Typhimurium To Potentiate Mucosal and Systemic Responses
Infect. Immun., October 1, 2005; 73(10): 6763 - 6770.
[Abstract] [Full Text] [PDF]


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J. Leukoc. Biol.Home page
H. Tsujimoto, T. Uchida, P. A. Efron, P. O. Scumpia, A. Verma, T. Matsumoto, S. K. Tschoeke, R. F. Ungaro, S. Ono, S. Seki, et al.
Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions
J. Leukoc. Biol., October 1, 2005; 78(4): 888 - 897.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
S. H. Rhee, E. Im, M. Riegler, E. Kokkotou, M. O'Brien, and C. Pothoulakis
Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation
PNAS, September 20, 2005; 102(38): 13610 - 13615.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
S. E. Applequist, E. Rollman, M. D. Wareing, M. Liden, B. Rozell, J. Hinkula, and H.-G. Ljunggren
Activation of Innate Immunity, Inflammation, and Potentiation of DNA Vaccination through Mammalian Expression of the TLR5 Agonist Flagellin
J. Immunol., September 15, 2005; 175(6): 3882 - 3891.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
G. Caron, D. Duluc, I. Fremaux, P. Jeannin, C. David, H. Gascan, and Y. Delneste
Direct Stimulation of Human T Cells via TLR5 and TLR7/8: Flagellin and R-848 Up-Regulate Proliferation and IFN-{gamma} Production by Memory CD4+ T Cells
J. Immunol., August 1, 2005; 175(3): 1551 - 1557.
[Abstract] [Full Text] [PDF]


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GutHome page
E Cario
BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2
Gut, August 1, 2005; 54(8): 1182 - 1193.
[Full Text] [PDF]


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Infect. Immun.Home page
S. K. Arora, A. N. Neely, B. Blair, S. Lory, and R. Ramphal
Role of Motility and Flagellin Glycosylation in the Pathogenesis of Pseudomonas aeruginosa Burn Wound Infections
Infect. Immun., July 1, 2005; 73(7): 4395 - 4398.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
E. Andersen-Nissen, K. D. Smith, K. L. Strobe, S. L. R. Barrett, B. T. Cookson, S. M. Logan, and A. Aderem
Evasion of Toll-like receptor 5 by flagellated bacteria
PNAS, June 28, 2005; 102(26): 9247 - 9252.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
L. A. Cummings, S. L. R. Barrett, W. D. Wilkerson, I. Fellnerova, and B. T. Cookson
FliC-Specific CD4+ T Cell Responses Are Restricted by Bacterial Regulation of Antigen Expression
J. Immunol., June 15, 2005; 174(12): 7929 - 7938.
[Abstract] [Full Text] [PDF]


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J ANIM SCIHome page
B. J. Johnson, S. S. Dritz, K. A. Skjolaas-Wilson, T. E. Burkey, and J. E. Minton
Interactive responses in gut immunity, and systemic and local changes in the insulin-like growth factor system in nursery pigs in response to Salmonella enterica serovar Typhimurium
J Anim Sci, June 1, 2005; 83(13_suppl): E48 - 56.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
M. Vijay-Kumar, J. R. Gentsch, W. J. Kaiser, N. Borregaard, M. K. Offermann, A. S. Neish, and A. T. Gewirtz
Protein Kinase R Mediates Intestinal Epithelial Gene Remodeling in Response to Double-Stranded RNA and Live Rotavirus
J. Immunol., May 15, 2005; 174(10): 6322 - 6331.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Gastrointest. Liver Physiol.Home page
K. L. Mumy and B. A. McCormick
Events at the Host-Microbial Interface of the Gastrointestinal Tract II. Role of the intestinal epithelium in pathogen-induced inflammation
Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G854 - G859.
[Abstract] [Full Text] [PDF]


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J. Immunol.Home page
M. T. Abreu, M. Fukata, and M. Arditi
TLR Signaling in the Gut in Health and Disease
J. Immunol., April 15, 2005; 174(8): 4453 - 4460.
[Abstract] [Full Text] [PDF]


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Infect. Immun.Home page
M. Iqbal, V. J. Philbin, G. S. K. Withanage, P. Wigley, R. K. Beal, M. J. Goodchild, P. Barrow, I. McConnell, D. J. Maskell, J. Young, et al.
Identification and Functional Characterization of Chicken Toll-Like Receptor 5 Reveals a Fundamental Role in the Biology of Infection with Salmonella enterica Serovar Typhimurium
Infect. Immun., April 1, 2005; 73(4): 2344 - 2350.
[Abstract] [Full Text] [PDF]


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Innate ImmunityHome page
M. W. Hornef and C. Bogdan
The role of epithelial Toll-like receptor expression in host defense and microbial tolerance
Innate Immunity, April 1, 2005; 11(2): 124 - 128.
[Abstract] [PDF]




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