Folia Biologica
Journal of Cellular and Molecular Biology, Charles University 

Crossref logo

Fol. Biol. 2005, 51, 148-156

https://doi.org/10.14712/fb2005051050148

Toll-like Receptors. I. Structure, Function and Their Ligands

F. Sandor, Milan Buc

Department of Immunology, Comenius University School of Medicine, Sasinkova, Bratislava, Slovakia

Received August 2005
Accepted September 2005

References

1. Ahmad-Nejad, P., Hacker, H., Rutz, M., Bauer, S., Vabulas, R. M., Wagner, H. (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958-1968. <https://doi.org/10.1002/1521-4141(200207)32:7<1958::AID-IMMU1958>3.0.CO;2-U>
2. Alexopoulou, L., Holt, A. C., Medzhitov, R., Flavell, R. A. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413, 732-738. <https://doi.org/10.1038/35099560>
3. Alexopoulou, L., Thomas, V., Schnare, M., Lobet, Y., Anguita, J., Schoen, R. T., Medzhitov, R., Fikrig, E., Flavell, R. A. (2002) Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1and TLR2deficient mice. Nat. Med. 8, 878-884. <https://doi.org/10.1038/nm732>
4. Aliprantis, A. O., Yang, R. B., Mark, M. R., Suggett, S., Devaux, B., Radolf, J. D., Klimpel, G. R., Godowski, P., Zychlinsky, A. (1999) Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 285, 736-739. <https://doi.org/10.1126/science.285.5428.736>
5. Bauer, S., Kirschning, C. J., Hacker, H., Redecke, V., Hausmann, S., Akira, S., Wagner, H., Lipford, G. B. (2001) Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc. Natl. Acad. Sci. USA 98, 9237-9242. <https://doi.org/10.1073/pnas.161293498>
6. Belvin, M. P., Anderson, K. V. (1996) A conserved signaling pathway: the Drosophila toll-dorsal pathway. Ann. Rev. Cell Dev. Biol. 12, 393-416. <https://doi.org/10.1146/annurev.cellbio.12.1.393>
7. Bernasconi, N. L., Onai, N.,Lanzavecchia, A. (2003) A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101, 4500-4504. <https://doi.org/10.1182/blood-2002-11-3569>
8. Bieback, K., Lien, E., Klagge, I. M., Avota, E., SchneiderSchaulies, J., Duprex, W. P., Wagner, H., Kirschning, C. J., Ter Meulen, V., Schneider-Schaulies, S. (2002) Hemagglutinin protein of wild-type measles virus activates toll-like receptor 2 signaling. J. Virol. 76, 8729-8736. <https://doi.org/10.1128/JVI.76.17.8729-8736.2002>
9. Brightbill, H. D., Libraty, D. H., Krutzik, S. R., Yang, R.-B., Belisle, J. T., Bleharski, J. R., Maitland, M., Norgard, M. V., Plevy, S. E., Smale, S. T., Brennan, P. J., Bloom, B. R., Godowski, P. J., Modlin, R. L. (1999) Host defense mechanisms triggered by microbial lipoproteins through Tolllike receptors. Science 285, 732-736. <https://doi.org/10.1126/science.285.5428.732>
10. Bucová, M. (2002) A role of cytokines in local and systemic inflammation, and septic shock. Vnitr. Lek. 48, 755-762.
11. Campos, M. A., Almeida, I. C., Takeuchi, O., Akira, S., Valente, E. P., Procopio, D. O., Travassos, L. R., Smith, J. A., Golenbock, D. T., Gazzinelli, R. T. (2001) Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 167, 416-423. <https://doi.org/10.4049/jimmunol.167.1.416>
12. Chuang, T., Ulevitch, R. J. (2001) Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochem. Biophys. Acta 1518, 157-161.
13. Coban, C., Ishii, K. J., Kawai, T., Hemmi, H., Sato, S., Uematsu, S., Yamamoto, M., Takeuchi, O., Itagaki, S., Kumar, N. (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozin. J. Exp. Med. 201, 19-25. <https://doi.org/10.1084/jem.20041836>
14. Compton, T., Kurt-Jones, E. A., Boehme, K. W., Belko, J., Latz, E., Golenbock, D. T., Finberg, R. W. (2003) Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J. Virol. 77, 4588-4596. <https://doi.org/10.1128/JVI.77.8.4588-4596.2003>
15. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S., Reis e Sousa, C. (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529-1531. <https://doi.org/10.1126/science.1093616>
16. Donnelly, M. A., Steiner, T. S. (2002) Two nonadjacent regions in enteroaggregative Escherichia coli flagellin are required for activation of toll-like receptor 5. J. Biol. Chem. 277, 40456-40461. <https://doi.org/10.1074/jbc.M206851200>
17. Du, X., Poltorak, A., Wei, Y., Beutler, B. (2000) Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur. Cytokine Netw. 11, 362-371.
18. Galdiero, M., Finamore, E., Rossano, F., Gambuzza, M., Catania, M. R., Teti, G., Midiri, A., Mancuso, G. (2004) Haemophilus influenzae porin induces Toll-like receptor 2-mediated cytokine production in human monocytes and mouse macrophages. Infect. Immun. 72, 1204-1209. <https://doi.org/10.1128/IAI.72.2.1204-1209.2004>
19. Gewirtz, A. T., Navas, T. A., Lyons, S., Godowski, P. J., Madara, J. L. (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J. Immunol. 167, 1882-1885. <https://doi.org/10.4049/jimmunol.167.4.1882>
20. Hajjar, A. M., O’Mahony, D. S., Ozinsky, A., Underhill, D. M., Aderem, A., Klebanoff, S. J., Wilson, C. B. (2001) Cutting edge: Functional interactions between Toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J. Immunol. 166, 15-19. <https://doi.org/10.4049/jimmunol.166.1.15>
21. 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. (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J. Exp. Med. 198, 1563-1572. <https://doi.org/10.1084/jem.20031220>
22. 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. (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099-10103. <https://doi.org/10.1038/35074106>
23. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., Akira, S. (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408, 740-745. <https://doi.org/10.1038/35047123>
24. Hemmi, H., Kaisho, T., Takeuchi, O., Sato, S., Sanjo, H., Hoshino, K., Horiuchi, T., Tomizawa, H., Takeda, K., Akira, S. (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196-200. <https://doi.org/10.1038/ni758>
25. Hirschfeld, M., Kirschning, C. J., Schwandner, R., Wesche, H., Weis, J. H., Wooten, R. M., Weis, J. J. (1999) Cutting edge: Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by Toll-like receptor 2. J. Immunol. 163, 2382-2386. <https://doi.org/10.4049/jimmunol.163.5.2382>
26. Hornung, V., Rothenfusser, S., Britsch, S., Krug, A., Jahrsdorfer, B., Giese, T., Endres, S., Hartmann, G. (2002) Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168, 4531-4537. <https://doi.org/10.4049/jimmunol.168.9.4531>
27. Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T., Takeda, Y., Takeda, K., Akira, S. (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162, 3749-3752. <https://doi.org/10.4049/jimmunol.162.7.3749>
28. Into, T., Kiura, K., Yasuda, M., Kataoka, H., Inoue, N., Hasebe, A., Takeda, K., Akira, S., Shibata, K. (2004) Stimulation of human Toll-like receptor (TLR) 2 and TLR6 with membrane lipoproteins of Mycoplasma fermentans induces apoptotic cell death after NF-kappa B activation. Cell Microbiol. 6, 187-199. <https://doi.org/10.1046/j.1462-5822.2003.00356.x>
29. Jarrossay, D., Napolitani, G., Colonna, M., Sallusto, F., Lanzavecchia, A. (2001) Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur. J. Immunol. 31, 3388-3393. <https://doi.org/10.1002/1521-4141(200111)31:11<3388::AID-IMMU3388>3.0.CO;2-Q>
30. Kariko, K., Ni, H., Capodici, J., Lamphier, M., Weissman, D. (2004) mRNA is an endogenous ligand for Toll-like receptor 3. J. Biol. Chem. 279, 12542-12550. <https://doi.org/10.1074/jbc.M310175200>
31. Kawai, T., Akira, S. (2005) Pathogen recognition with Toll like receptors. Curr. Opin. Immunol. 17, 338-344. <https://doi.org/10.1016/j.coi.2005.02.007>
32. Krug, A., Towarowski, A., Britsch, S., Rothenfusser, S., Hornung, V., Bals, R., Giese, T., Engelmann, H., Endres, S., Krieg, A. M., Hartmann, G. (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with CD40 ligand to induce high amounts of IL-12. Eur. J. Immunol. 31, 3026-3037. <https://doi.org/10.1002/1521-4141(2001010)31:10<3026::AID-IMMU3026>3.0.CO;2-H>
33. Kurt-Jones, E. A., Popova, L., Kwinn, L., Haynes, L. M., Jones, L. P., Tripp, R. A., Walsh, E. E., Freeman, M. W., Golenbock, D. T., Anderson, L. J., Finberg, R. W. (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1, 398-401. <https://doi.org/10.1038/80833>
34. Kurt-Jones, E. A., Chan, M., Zhou, S., Wang, J., Reed, G., Bronson, R., Arnold, M. M., Knipe, D. M., Finberg, R. W. (2004) Herpes simplex virus 1 interaction with Toll-like receptor 2 contributes to lethal encephalitis. Proc. Natl. Acad. Sci. USA 101, 1315-1320. <https://doi.org/10.1073/pnas.0308057100>
35. Latz, E., Schoenemeyer, A., Visintin, A., Fitzgerald, K. A., Monks, B. G., Knetter, C. F., Lien, E., Nilsen, N. J., Espevik, T., Golenbock, D. T. (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190-198. <https://doi.org/10.1038/ni1028>
36. Lee, S. K., Stack, A., Katzowitsch, E., Aizawa, S. I., Suerbaum, S., Josenhans, C. (2003) Helicobacter pylori flagellins have very low intrinsic activity to stimulate human gastric epithelial cells via TLR5. Microbes Infect. 5, 1345-1356. <https://doi.org/10.1016/j.micinf.2003.09.018>
37. Lien, E., Sellati, T. J., Yoshimura, A., Flo, T. H., Rawadi, G., Finberg, R. W., Carroll, J. D., Espevik, T., Ingalls, R. R., Radolf, J. D., Golenbock, D. T. (1999) Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J. Biol. Chem. 274, 33419-33425. <https://doi.org/10.1074/jbc.274.47.33419>
38. Lin, L., Gerth, A. J., Peng, S. L. (2004) CpG DNA redirects class-switching towards „Th1-like“ Ig isotype production via TLR9 and MyD88. Eur. J. Immunol. 34, 1483-1487. <https://doi.org/10.1002/eji.200324736>
39. Lund, J., Sato, A., Akira, S., Medzhitov, R., Iwasaki, A. (2003) Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513-520. <https://doi.org/10.1084/jem.20030162>
40. Maaser, C., Heidemann, J., von Eiff, C., Lugering, A., Spahn, T. W., Binion, D. G., Domschke, W., Lugering, N., Kucharzik, T. (2004) Human intestinal microvascular endothelial cells express Toll-like receptor 5: a binding partner for bacterial flagellin. J. Immunol. 172, 5056-5062. <https://doi.org/10.4049/jimmunol.172.8.5056>
41. Massari, P., Henneke, P., Ho, Y., Latz, E., Golenbock, D. T., Wetzler, L. M. (2002) Cutting edge: Immune stimulation by Neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168, 1533-1537. <https://doi.org/10.4049/jimmunol.168.4.1533>
42. Means, T. K., Wang, S., Lien, E., Yoshimura, A., Golenbock, D. T., Fenton, M. J. (1999) Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163, 3920-3927. <https://doi.org/10.4049/jimmunol.163.7.3920>
43. Medzhitov, R., Preston-Hurlburt, P., Janeway, C. A. J. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397. <https://doi.org/10.1038/41131>
44. Netea, M. G., van Deuren, M., Kullberg, B. J., Cavaillon, J. M., Van der Meer, J. W. (2002) Does the shape of lipid A determine the interaction of LPS with Toll-like receptors? Trends Immunol. 23, 135-139. <https://doi.org/10.1016/S1471-4906(01)02169-X>
45. Ogawa, T., Asai, Y., Hashimoto, M., Takeuchi, O., Kurita, T., Yoshikai, Y., Miyake, K., Akira, S. (2002) Cell activation by Porphyromonas gingivalis lipid A molecule through Toll-like receptor 4and myeloid differentiation factor 88dependent signaling pathway. Int. Immunol. 14, 1325-1332. <https://doi.org/10.1093/intimm/dxf097>
46. Ozinsky, A., Underhill, D. M., Fontenot, J. D., Hajjar, A. M., Smith, K. D., Wilson, C. B., Schroeder, L., Aderem, A. (2000) 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 97, 13766-13771. <https://doi.org/10.1073/pnas.250476497>
47. Poeck, H., Wagner, M., Battiany, J., Rothenfusser, S., Wellisch, D., Hornung, V., Jahrsdorfer, B., Giese, T., Endres, S., Hartmann, G. (2004) Plasmacytoid dendritic cells, antigen, and CpG-C license human B cells for plasma cell differentiation and immunoglobulin production in the absence of T-cell help. Blood 103, 3058-3064. <https://doi.org/10.1182/blood-2003-08-2972>
48. Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., Beutler, B. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085-2088. <https://doi.org/10.1126/science.282.5396.2085>
49. Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A., Bazan, J. F. (1998) A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. USA 95, 588-593. <https://doi.org/10.1073/pnas.95.2.588>
50. Sandor, F., Latz, E., Re, F., Mandell, L., Repik, G., Golenbock, D. T., Espevik, T., Kurt-Jones, E. A., Finberg, R. W. (2003) Importance of extraand intracellular domains of TLR1 and TLR2 in NFkappa B signaling. J. Cell Biol. 162, 1099-10110. <https://doi.org/10.1083/jcb.200304093>
51. Schmidt, K. N., Leung, B., Kwong, M., Zarember, K. A., Satyal, S., Navas, T. A., Wang, F., Godowski, P. J. (2004) APC-independent activation of NK cells by the Toll-like receptor 3 agonist double-stranded RNA. J. Immunol. 172, 138-143. <https://doi.org/10.4049/jimmunol.172.1.138>
52. Schwadner, R., Dziarski, R., Wesche, H., Rothe, M., Kirschning, C. J. (1999) Peptidoglycanand lipoteichoic acidinduced cell activation is mediated by Toll-like receptor 2. J. Biol. Chem. 274, 17406-17409. <https://doi.org/10.1074/jbc.274.25.17406>
53. Shimazu, R., Akashi, S., Ogata, H., Nagai, Y., Fukudome, K., Miyake, K., Kimoto, M. (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777-1782. <https://doi.org/10.1084/jem.189.11.1777>
54. Smiley, S. T., King, J. A., Hancock, W. W. (2001) Fibrinogen stimulates macrophage chemokine secretion through tolllike receptor 4. J. Immunol. 167, 2887-2894. <https://doi.org/10.4049/jimmunol.167.5.2887>
55. Smith, K. D., Andersen-Nissen, E., Hayashi, F., Strobe, K., Bergman, M. A., Barrett, S. L., Cookson, B. T., Aderem, A. (2003) Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol. 4, 1247-1253. <https://doi.org/10.1038/ni1011>
56. Steere, A. C., Sikand, V. K., Meurice, F., Parenti, D. L., Fikrig, E., Schoen, R. T., Nowakowski, J., Schmid, C. H., Laukamp, S., Buscarino, C., Krause, D. S. (1998) Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group. N. Engl. J. Med. 339, 209-215. <https://doi.org/10.1056/NEJM199807233390401>
57. Takeuchi, O., Kawai, T., Sanjo, H., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Takeda, K., Akira, S. (1999) TLR6: A novel member of an expanding toll-like receptor family. Gene 231, 59-65. <https://doi.org/10.1016/S0378-1119(99)00098-0>
58. Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R. L. S. A. (2002) Role of TLR1 in mediating immune response to microbial lipoproteins. J. Immunol. 169, 10-14. <https://doi.org/10.4049/jimmunol.169.1.10>
59. Taylor, K. R., Trowbridge, J. M., Rudisill, J. A., Termeer, C. C., Simon, J. C., Gallo, R. L. (2004) Hyaluronan fragments stimulate dermal endothelial recognition of injury through TLR4. J. Biol. Chem. 279, 17079-17084. <https://doi.org/10.1074/jbc.M310859200>
60. Termeer, C., Benedix, F., Sleeman, J., Fieber, C., Voith, U., Ahrens, T., Miyake, K., Freudenberg, M., Galanos, C., Simon, J. C. (2002) Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195, 99-111. <https://doi.org/10.1084/jem.20001858>
61. Tobias, P. S., Soldau, K., Ulevitch, R. J. (1986) Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum. J. Exp. Med. 164, 777-793. <https://doi.org/10.1084/jem.164.3.777>
62. Underhill, D. M., Ozinsky, A., Hajjar, A. M., Stevens, A., Wilson, C. B., Bassetti, M., Aderem, A. (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811-815. <https://doi.org/10.1038/44605>
63. Vabulas, R. M., Ahmad-Nejad, P., Ghose, S., Kirschning, C. J., Issels, R. D., Wagner, H. (2002) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107-15112. <https://doi.org/10.1074/jbc.M111204200>
64. Viriyakosol, S., Kirkland, T., Soldau, K., Tobias, P. (2000) MD-2 binds to bacterial lipopolysaccharide. J. Endotoxin Res. 6, 489-491. <https://doi.org/10.1177/09680519000060060201>
65. Werts, C., Tapping, R. I., Mathison, J. C., Chuang, T. H., Kravchenko, V., Saint Girons, I., Haake, D. A., Godowski, P. J., Hayashi, F., Ozinsky, A., Underhill, D. M., Kirschning, C. J., Wagner, H., Aderem, A., Tobias, P. S., Ulevitch, R. J. (2001) Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. Nat. Immunol. 2, 346-352. <https://doi.org/10.1038/86354>
66. Yarovinsky, F., Zhang, D., Andersen, J. F., Bannenmberg, G. L., Serhan, C. N., Hayden, M. S., Hieny, S., Sutterwala, F. S., Flavell, R. A., Ghash, S., Sher, A. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308, 1626-1629. <https://doi.org/10.1126/science.1109893>
67. Yoshimura, A., Lien, E., Ingalls, R. R., Tuomanen, E., Dziarski, R., Golenbock, D. (1999) Cutting edge: Recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 165, 1-5. <https://doi.org/10.4049/jimmunol.163.1.1>
68. Zhang, D., Zhang, G., Hayden, M. S., Greenblatt, M. B., Bussey, C., Flavell, R. A., Ghosh, S. (2004) Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522-1526. <https://doi.org/10.1126/science.1094351>
front cover

ISSN 0015-5500 (Print) ISSN 2533-7602 (Online)

Open access journal

Submissions

Archive