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Gene Review

TLR5  -  toll-like receptor 5

Homo sapiens

Synonyms: FLJ10052, MELIOS, MGC126430, MGC126431, SLE1, ...
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Disease relevance of TLR5


High impact information on TLR5

  • Our data suggest that TLR5, a member of the evolutionarily conserved Toll-like receptor family, has evolved to permit mammals specifically to detect flagellated bacterial pathogens [6].
  • With deletional, insertional and alanine-scanning mutagenesis, we precisely mapped the TLR5 recognition site on flagellin to a cluster of 13 amino acid residues that participate in intermolecular interactions within flagellar protofilaments and that are required for bacterial motility [7].
  • A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease [8].
  • In addition, TLR2, TLR5 and TLR8 modulate the suppressive activity of naturally occurring CD25(+)CD4(+) regulatory T cells [9].
  • We observed an induction of mRNA for TLR2, TLR4, and TLR5 in inflammation-associated macrophages [10].

Chemical compound and disease context of TLR5


Biological context of TLR5


Anatomical context of TLR5

  • Here we dissected the biochemical mechanism by which TLR5 engagement mediates phosphatidylinositol 3-kinase (PI3K) activation in colonic epithelial cells [18].
  • These results demonstrate that TLR1 through TLR5 mRNAs are differentially expressed and regulated in human leukocytes [19].
  • Finally, DCs isolated from mouse spleens or bone marrows were shown to not express TLR5 and were not responsive to flagellin stimulation [20].
  • There was evidence for participation of asialoGM1 and TLR2 as well as TLR5 in the response to flagella, and increased asialoGM1 correlated directly with increased signaling [21].
  • Immunostaining with TLR5 antibodies showed that TLR5 was expressed in HAECs and on the apical surface of the human trachea epithelium [2].

Associations of TLR5 with chemical compounds


Physical interactions of TLR5

  • Signaling of flagellin via TLR5/TLR4 heteromeric complexes enhances the diversity of the response, likely by engaging MyD88-independent adaptors to activate the interferon pathway [27].

Regulatory relationships of TLR5

  • TLR2 DN or TLR5 DN mutations inhibited interleukin-8 induction by 78% and 35%, respectively (P < 0.001 for each) [21].
  • TLR4 was strongly expressed by tumor cells of 17 out of 22 and TLR5 by tumor cells of all 22 patients with gastric carcinoma [28].
  • These results suggest that gangliosides act as co-receptors with TLR5 for FliC and promote hBD-2 expression via mitogen-activated protein kinase [29].
  • Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells [30].
  • Conversely, overexpression of dominant-negative TLR5 alleles only partially blocks NF-kappa B activation by flagellin [31].

Other interactions of TLR5

  • Thus, in non-transformed human colonocytes, MEK activation following flagellin/TLR5 engagement is a key modulator for NFkappaB-independent, IL-8 and MIP3alpha expression [32].
  • LPS-induced cross-tolerance to flagellin is also associated with a block in IRAK release from TLR5 [15].
  • Little or no TLR5 and RP105 mRNA expression was observed in HUVEC, whereas a moderate level was detected in PBMC and THP-1 cells [33].
  • Similarly, in HIEC transfected with a plasmid encoding dominant negative TLR5, no CARD15 induction was observed after K12 contact [34].
  • However, in H. pylori gastritis TLR5 and TLR9 expression on the gastric epithelium changed to an exclusive basolateral localization without detectable expression at the apical pole [35].

Analytical, diagnostic and therapeutic context of TLR5


  1. Borrelia burgdorferi lipoprotein-mediated TLR2 stimulation causes the down-regulation of TLR5 in human monocytes. Cabral, E.S., Gelderblom, H., Hornung, R.L., Munson, P.J., Martin, R., Marques, A.R. J. Infect. Dis. (2006) [Pubmed]
  2. Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Zhang, Z., Louboutin, J.P., Weiner, D.J., Goldberg, J.B., Wilson, J.M. Infect. Immun. (2005) [Pubmed]
  3. Normal keratinocytes express Toll-like receptors (TLRs) 1, 2 and 5: modulation of TLR expression in chronic plaque psoriasis. Baker, B.S., Ovigne, J.M., Powles, A.V., Corcoran, S., Fry, L. Br. J. Dermatol. (2003) [Pubmed]
  4. Epithelial toll-like receptor 5 is constitutively localized in the mouse cecum and exhibits distinctive down-regulation during experimental colitis. Ortega-Cava, C.F., Ishihara, S., Rumi, M.A., Aziz, M.M., Kazumori, H., Yuki, T., Mishima, Y., Moriyama, I., Kadota, C., Oshima, N., Amano, Y., Kadowaki, Y., Ishimura, N., Kinoshita, Y. Clinical and vaccine immunology : CVI. (2006) [Pubmed]
  5. Innate immunity mediated by TLR5 as a novel antiinflammatory target for cystic fibrosis lung disease. Blohmke, C.J., Victor, R.E., Hirschfeld, A.F., Elias, I.M., Hancock, D.G., Lane, C.R., Davidson, A.G., Wilcox, P.G., Smith, K.D., Overhage, J., Hancock, R.E., Turvey, S.E. J. Immunol. (2008) [Pubmed]
  6. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., Aderem, A. Nature (2001) [Pubmed]
  7. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Smith, K.D., Andersen-Nissen, E., Hayashi, F., Strobe, K., Bergman, M.A., Barrett, S.L., Cookson, B.T., Aderem, A. Nat. Immunol. (2003) [Pubmed]
  8. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. Hawn, T.R., Verbon, A., Lettinga, K.D., Zhao, L.P., Li, S.S., Laws, R.J., Skerrett, S.J., Beutler, B., Schroeder, L., Nachman, A., Ozinsky, A., Smith, K.D., Aderem, A. J. Exp. Med. (2003) [Pubmed]
  9. Expression and function of Toll-like receptors in T lymphocytes. Kabelitz, D. Curr. Opin. Immunol. (2007) [Pubmed]
  10. Toll-like receptors 2 and 4 are up-regulated during intestinal inflammation. Hausmann, M., Kiessling, S., Mestermann, S., Webb, G., Spöttl, T., Andus, T., Schölmerich, J., Herfarth, H., Ray, K., Falk, W., Rogler, G. Gastroenterology (2002) [Pubmed]
  11. Gene expression clusters of a lipopolysaccharide-stimulated pathway in peripheral blood monocytes of Japanese patients with Crohn's disease. Naito, Y., Takagi, T., Mizushima, K., Ueta, M., Kinoshita, S., Handa, O., Kokura, S., Ichikawa, H., Yoshida, N., Yoshikawa, T. Aliment. Pharmacol. Ther. (2006) [Pubmed]
  12. Identification of a transcript encoding a soluble form of toll-like receptor 5 (TLR5) in Atlantic salmon during Aeromonas salmonicida infection. Tsoi, S., Park, K.C., Kay, H.H., O'Brien, T.J., Podor, E., Sun, G., Douglas, S.E., Brown, L.L., Johnson, S.C. Vet. Immunol. Immunopathol. (2006) [Pubmed]
  13. Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. Smith, M.F., Mitchell, A., Li, G., Ding, S., Fitzmaurice, A.M., Ryan, K., Crowe, S., Goldberg, J.B. J. Biol. Chem. (2003) [Pubmed]
  14. Cooperative interactions between flagellin and SopE2 in the epithelial interleukin-8 response to Salmonella enterica serovar typhimurium infection. Huang, F.C., Werne, A., Li, Q., Galyov, E.E., Walker, W.A., Cherayil, B.J. Infect. Immun. (2004) [Pubmed]
  15. Gram-negative flagellin-induced self-tolerance is associated with a block in interleukin-1 receptor-associated kinase release from toll-like receptor 5. Mizel, S.B., Snipes, J.A. J. Biol. Chem. (2002) [Pubmed]
  16. A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Hawn, T.R., Wu, H., Grossman, J.M., Hahn, B.H., Tsao, B.P., Aderem, A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  17. A family of human receptors structurally related to Drosophila Toll. Rock, F.L., Hardiman, G., Timans, J.C., Kastelein, R.A., Bazan, J.F. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  18. Role of MyD88 in phosphatidylinositol 3-kinase activation by flagellin/toll-like receptor 5 engagement in colonic epithelial cells. Rhee, S.H., Kim, H., Moyer, M.P., Pothoulakis, C. J. Biol. Chem. (2006) [Pubmed]
  19. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. Muzio, M., Bosisio, D., Polentarutti, N., D'amico, G., Stoppacciaro, A., Mancinelli, R., van't Veer, C., Penton-Rol, G., Ruco, L.P., Allavena, P., Mantovani, A. J. Immunol. (2000) [Pubmed]
  20. The Toll-like receptor 5 stimulus bacterial flagellin induces maturation and chemokine production in human dendritic cells. Means, T.K., Hayashi, F., Smith, K.D., Aderem, A., Luster, A.D. J. Immunol. (2003) [Pubmed]
  21. Pseudomonas aeruginosa flagella activate airway epithelial cells through asialoGM1 and toll-like receptor 2 as well as toll-like receptor 5. Adamo, R., Sokol, S., Soong, G., Gomez, M.I., Prince, A. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  22. AsialoGM1-Mediated IL-8 Release by Human Corneal Epithelial Cells Requires Coexpression of TLR5. Du, J.W., Zhang, F., Cap??-Aponte, J.E., Tachado, S.D., Zhang, J., Yu, F.S., Sack, R.A., Koziel, H., Reinach, P.S. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  23. Identification of a sequence in human toll-like receptor 5 required for the binding of Gram-negative flagellin. Mizel, S.B., West, A.P., Hantgan, R.R. J. Biol. Chem. (2003) [Pubmed]
  24. Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. Gewirtz, A.T., Navas, T.A., Lyons, S., Godowski, P.J., Madara, J.L. J. Immunol. (2001) [Pubmed]
  25. Cutting Edge: Loss of TLR2, TLR4, and TLR5 on Langerhans Cells Abolishes Bacterial Recognition. van der Aar, A.M., Sylva-Steenland, R.M., Bos, J.D., Kapsenberg, M.L., de Jong, E.C., Teunissen, M.B. J. Immunol. (2007) [Pubmed]
  26. Bacterial flagellin inhibits T cell receptor-mediated activation of T cells by inducing suppressor of cytokine signalling-1 (SOCS-1). Okugawa, S., Yanagimoto, S., Tsukada, K., Kitazawa, T., Koike, K., Kimura, S., Nagase, H., Hirai, K., Ota, Y. Cell. Microbiol. (2006) [Pubmed]
  27. Effects of flagellin on innate and adaptive immunity. Honko, A.N., Mizel, S.B. Immunol. Res. (2005) [Pubmed]
  28. Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Schmausser, B., Andrulis, M., Endrich, S., Müller-Hermelink, H.K., Eck, M. Int. J. Med. Microbiol. (2005) [Pubmed]
  29. Gangliosides act as co-receptors for Salmonella enteritidis FliC and promote FliC induction of human beta-defensin-2 expression in Caco-2 cells. Ogushi, K., Wada, A., Niidome, T., Okuda, T., Llanes, R., Nakayama, M., Nishi, Y., Kurazono, H., Smith, K.D., Aderem, A., Moss, J., Hirayama, T. J. Biol. Chem. (2004) [Pubmed]
  30. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. Crellin, N.K., Garcia, R.V., Hadisfar, O., Allan, S.E., Steiner, T.S., Levings, M.K. J. Immunol. (2005) [Pubmed]
  31. Flagellin acting via TLR5 is the major activator of key signaling pathways leading to NF-kappa B and proinflammatory gene program activation in intestinal epithelial cells. Tallant, T., Deb, A., Kar, N., Lupica, J., de Veer, M.J., DiDonato, J.A. BMC Microbiol. (2004) [Pubmed]
  32. MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. Rhee, S.H., Keates, A.C., Moyer, M.P., Pothoulakis, C. J. Biol. Chem. (2004) [Pubmed]
  33. Possible involvement of toll-like receptor 4 in endothelial cell activation of larger vessels in response to lipopolysaccharide. Hijiya, N., Miyake, K., Akashi, S., Matsuura, K., Higuchi, Y., Yamamoto, S. Pathobiology (2002) [Pubmed]
  34. Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop. Begue, B., Dumant, C., Bambou, J.C., Beaulieu, J.F., Chamaillard, M., Hugot, J.P., Goulet, O., Schmitz, J., Philpott, D.J., Cerf-Bensussan, N., Ruemmele, F.M. J. Cell. Physiol. (2006) [Pubmed]
  35. Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Schmausser, B., Andrulis, M., Endrich, S., Lee, S.K., Josenhans, C., Müller-Hermelink, H.K., Eck, M. Clin. Exp. Immunol. (2004) [Pubmed]
  36. Involvement of Toll-like receptor 5 in the recognition of flagellated bacteria. Feuillet, V., Medjane, S., Mondor, I., Demaria, O., Pagni, P.P., Galán, J.E., Flavell, R.A., Alexopoulou, L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  37. Human intestinal microvascular endothelial cells express Toll-like receptor 5: a binding partner for bacterial flagellin. Maaser, C., Heidemann, J., von Eiff, C., Lugering, A., Spahn, T.W., Binion, D.G., Domschke, W., Lugering, N., Kucharzik, T. J. Immunol. (2004) [Pubmed]
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