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Gene Review

TLR3  -  toll-like receptor 3

Homo sapiens

Synonyms: CD283, IIAE2, Toll-like receptor 3
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Disease relevance of TLR3


Psychiatry related information on TLR3


High impact information on TLR3

  • TLR3-deficient (TLR3-/-) mice showed reduced responses to polyinosine-polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines [7].
  • In the presence of CD14, TLR3-mediated signal transduction events are amplified [8].
  • Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs [9].
  • Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts [9].
  • In this issue of Immunity, Kariko et al (2005) suggest that the innate immune recognition of RNA by TLR3, TLR7, or TLR8 is in fact controlled by modification of nucleotides, including methylation [10].

Chemical compound and disease context of TLR3


Biological context of TLR3

  • p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells [12].
  • In our current study, we show that activation of IFN/viral response gene expression in primary macrophage cells is stronger and prolonged with TLR3 stimulation compared with that of TLR4 [13].
  • TLR3 on dendritic cells recognize double-stranded (ds) RNA and then signal increases in cytokines and recognition molecules important for immune cell interactions [4].
  • Further studies revealed that TLR3 knockdown significantly reduced NF-kappaB/RelA transcription by its ability to block the activating phosphorylation of NF-kappaB/RelA at serine residue 276 [14].
  • Also, TLR3 but not TLR4 activation on astrocytes induces expression of several factors involved in neuroprotection and down-regulation of inflammation rather than in the onset of traditional pro-inflammatory reactions [15].

Anatomical context of TLR3

  • TLR1 and TLR3 were only detectable in blood monocytes [16].
  • The occurrence of dsRNA-induced signaling and functional events closely correlates with the TLR3 mRNAprofile in different NK cell populations [12].
  • Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10-all the TLRs except TLR3 [17].
  • We established that TLR3 is constitutively expressed in human alveolar and bronchial epithelial cells, and we describe its intracellular localization [1].
  • Astrocytes express both cell surface and intracellular TLR3 [18].

Associations of TLR3 with chemical compounds

  • Polyinosinic-polycytidilic acid (poly(I:C)) (TLR3 agonist) stimulates TNFalpha expression in macrophages from both C57BL/10ScSn and C57BL/10ScN mice, but has little effect on VEGF expression in the presence of adenosine or A(2A)R agonists [19].
  • First, treatment of monocyte-derived dendritic cells (DC) with wortmannin or LY294002 was found to enhance IFN-beta expression upon TLR3 or TLR4 engagement [20].
  • The time course showed that histamine induced TLR3 mRNA expression was initiated at 30min, nearly reached peak levels after 2h and was sustained at least until 12h [21].
  • 2'-O-methyl or 2'-fluoro modification of cytidylic acid abolished the IFN-beta-inducing ability of the poly(I:C) duplex, and these modified dsRNAs inhibited poly(I:C)-induced TLR3-mediated IFN-beta production by fibroblasts and DCs [22].
  • To understand the response of murine uterine natural killer (uNK) cells to Toll-like receptor (TLR) 3 agonist at the early gestation stage, CBAxDBA/2 mice were intraperitoneally (i.p.) injected with polyinosinic-polycytidylic acid (poly I:C), the specific TLR3 agonist, at a dose of 10 mug/g BW or PBS at gestation day (gd) 6 [23].
  • TNFalpha was found secreted by TLR3-stimulated RA-SF [24].
  • To elucidate the pH-dependent binding mechanism of TLR3 at the structural level, we focused on three highly conserved histidine residues clustered at the N-terminal region of the TLR3 ECD: His39 in the N-cap region, His60 in LRR1, and His108 in LRR3 [25].

Co-localisations of TLR3

  • Despite their using distinct regulatory elements for intracellular localization, TLR3 was found to co-localize with TLR7 [26].

Regulatory relationships of TLR3

  • In particular, expression of TLR3 transcripts is restricted to DC that are the only elements which express the full TLR repertoire [27].
  • Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters [28].
  • We further found that TLR3 induction following RSV infection was regulated by RIG-I-dependent IFN-beta secreted from infected airway epithelial cells and was mediated by both IFN response-stimulated element (ISRE) and signal transducer and activator of transcription (STAT) sites in its proximal promoter [14].
  • Thus, the STAT1-SOCS1 pathway regulates the innate immune response via TLR3 signaling in epidermal keratinocytes [29].
  • In conclusion, our results suggest that IFN-alpha-induced up-regulation of TLR3 expression is involved in dsRNA activated antiviral response in human epithelial and endothelial cells [30].

Other interactions of TLR3

  • IRF3 mediates a TLR3/TLR4-specific antiviral gene program [31].
  • We demonstrate that, when the TLR3 pathway is stimulated, the levels of phosphorylated IRF3 are reduced in the presence of W protein but not V protein, confirming the differential effects of these proteins and illustrating that W protein-mediated inhibition is due to a loss of active IRF3 [32].
  • In contrast, enhanced CXCL11 secretion was only obtained when IFN-gamma was combined with TLR3 ligand [33].
  • Only TLR9 ligand CpG-oligodeoxynucleotides (ODNs) and TLR3 ligand poly-I:C could additionally induce type I IFNs [34].
  • CD8+ cells from infected tonsils expressed higher levels of TLR2, TLR3 and TLR5 compared to control [35].

Analytical, diagnostic and therapeutic context of TLR3


  1. Involvement of toll-like receptor 3 in the immune response of lung epithelial cells to double-stranded RNA and influenza A virus. Guillot, L., Le Goffic, R., Bloch, S., Escriou, N., Akira, S., Chignard, M., Si-Tahar, M. J. Biol. Chem. (2005) [Pubmed]
  2. Human Langerhans Cells Express a Specific TLR Profile and Differentially Respond to Viruses and Gram-Positive Bacteria. Flacher, V., Bouschbacher, M., Verron??se, E., Massacrier, C., Sisirak, V., Berthier-Vergnes, O., de Saint-Vis, B., Caux, C., Dezutter-Dambuyant, C., Lebecque, S., Valladeau, J. J. Immunol. (2006) [Pubmed]
  3. Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM. Hise, A.G., Daehnel, K., Gillette-Ferguson, I., Cho, E., McGarry, H.F., Taylor, M.J., Golenbock, D.T., Fitzgerald, K.A., Kazura, J.W., Pearlman, E. J. Immunol. (2007) [Pubmed]
  4. Thyrocytes express a functional toll-like receptor 3: overexpression can be induced by viral infection and reversed by phenylmethimazole and is associated with Hashimoto's autoimmune thyroiditis. Harii, N., Lewis, C.J., Vasko, V., McCall, K., Benavides-Peralta, U., Sun, X., Ringel, M.D., Saji, M., Giuliani, C., Napolitano, G., Goetz, D.J., Kohn, L.D. Mol. Endocrinol. (2005) [Pubmed]
  5. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Cario, E., Podolsky, D.K. Infect. Immun. (2000) [Pubmed]
  6. Expression of Toll-like receptor 3 in the human cerebellar cortex in rabies, herpes simplex encephalitis, and other neurological diseases. Jackson, A.C., Rossiter, J.P., Lafon, M. J. Neurovirol. (2006) [Pubmed]
  7. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Alexopoulou, L., Holt, A.C., Medzhitov, R., Flavell, R.A. Nature (2001) [Pubmed]
  8. CD14: chaperone or matchmaker? Finberg, R.W., Kurt-Jones, E.A. Immunity (2006) [Pubmed]
  9. Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses. Yang, K., Puel, A., Zhang, S., Eidenschenk, C., Ku, C.L., Casrouge, A., Picard, C., von Bernuth, H., Senechal, B., Plancoulaine, S., Al-Hajjar, S., Al-Ghonaium, A., Maródi, L., Davidson, D., Speert, D., Roifman, C., Garty, B.Z., Ozinsky, A., Barrat, F.J., Coffman, R.L., Miller, R.L., Li, X., Lebon, P., Rodriguez-Gallego, C., Chapel, H., Geissmann, F., Jouanguy, E., Casanova, J.L. Immunity (2005) [Pubmed]
  10. TLR ignores methylated RNA? Ishii, K.J., Akira, S. Immunity (2005) [Pubmed]
  11. Cutting Edge: TLR3 Stimulation Suppresses Experimental Autoimmune Encephalomyelitis by Inducing Endogenous IFN-beta. Touil, T., Fitzgerald, D., Zhang, G.X., Rostami, A., Gran, B. J. Immunol. (2006) [Pubmed]
  12. p38 MAPK activation controls the TLR3-mediated up-regulation of cytotoxicity and cytokine production in human NK cells. Pisegna, S., Pirozzi, G., Piccoli, M., Frati, L., Santoni, A., Palmieri, G. Blood (2004) [Pubmed]
  13. Toll-like receptor 3 mediates a more potent antiviral response than Toll-like receptor 4. Doyle, S.E., O'Connell, R., Vaidya, S.A., Chow, E.K., Yee, K., Cheng, G. J. Immunol. (2003) [Pubmed]
  14. Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells. Liu, P., Jamaluddin, M., Li, K., Garofalo, R.P., Casola, A., Brasier, A.R. J. Virol. (2007) [Pubmed]
  15. Identification of soluble CD14 as an endogenous agonist for Toll-like receptor 2 on human astrocytes by genome-scale functional screening of glial cell derived proteins. Bsibsi, M., Bajramovic, J.J., Van Duijvenvoorden, E., Persoon, C., Ravid, R., Van Noort, J.M., Vogt, M.H. Glia (2007) [Pubmed]
  16. 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]
  17. Toll-like receptors stimulate human neutrophil function. Hayashi, F., Means, T.K., Luster, A.D. Blood (2003) [Pubmed]
  18. TLR signaling tailors innate immune responses in human microglia and astrocytes. Jack, C.S., Arbour, N., Manusow, J., Montgrain, V., Blain, M., McCrea, E., Shapiro, A., Antel, J.P. J. Immunol. (2005) [Pubmed]
  19. An angiogenic switch in macrophages involving synergy between Toll-like receptors 2, 4, 7, and 9 and adenosine A(2A) receptors. Pinhal-Enfield, G., Ramanathan, M., Hasko, G., Vogel, S.N., Salzman, A.L., Boons, G.J., Leibovich, S.J. Am. J. Pathol. (2003) [Pubmed]
  20. Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-kappa B activation and IFN-beta synthesis downstream of Toll-like receptor 3 and 4. Aksoy, E., Vanden Berghe, W., Detienne, S., Amraoui, Z., Fitzgerald, K.A., Haegeman, G., Goldman, M., Willems, F. Eur. J. Immunol. (2005) [Pubmed]
  21. Modulation of expression and function of Toll-like receptor 3 in A549 and H292 cells by histamine. Hou, Y.F., Zhou, Y.C., Zheng, X.X., Wang, H.Y., Fu, Y.L., Fang, Z.M., He, S.H. Mol. Immunol. (2006) [Pubmed]
  22. Interferon-beta induction through toll-like receptor 3 depends on double-stranded RNA structure. Okahira, S., Nishikawa, F., Nishikawa, S., Akazawa, T., Seya, T., Matsumoto, M. DNA Cell Biol. (2005) [Pubmed]
  23. Toll-like receptor 3 agonist enhances IFN-gamma and TNF-alpha production by murine uterine NK cells. Zhang, J., Sun, R., Wei, H., Wu, D., Tian, Z. Int. Immunopharmacol. (2007) [Pubmed]
  24. Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. Lundberg, A.M., Drexler, S.K., Monaco, C., Williams, L.M., Sacre, S.M., Feldmann, M., Foxwell, B.M. Blood (2007) [Pubmed]
  25. Modulation of double-stranded RNA recognition by the N-terminal histidine-rich region of the human toll-like receptor 3. Fukuda, K., Watanabe, T., Tokisue, T., Tsujita, T., Nishikawa, S., Hasegawa, T., Seya, T., Matsumoto, M. J. Biol. Chem. (2008) [Pubmed]
  26. TLR3 and TLR7 are targeted to the same intracellular compartments by distinct regulatory elements. Nishiya, T., Kajita, E., Miwa, S., Defranco, A.L. J. Biol. Chem. (2005) [Pubmed]
  27. 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]
  28. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K., Akira, S. J. Immunol. (2002) [Pubmed]
  29. SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes. Dai, X., Sayama, K., Yamasaki, K., Tohyama, M., Shirakata, Y., Hanakawa, Y., Tokumaru, S., Yahata, Y., Yang, L., Yoshimura, A., Hashimoto, K. J. Invest. Dermatol. (2006) [Pubmed]
  30. IFN-alpha enhances TLR3-mediated antiviral cytokine expression in human endothelial and epithelial cells by up-regulating TLR3 expression. Tissari, J., Sirén, J., Meri, S., Julkunen, I., Matikainen, S. J. Immunol. (2005) [Pubmed]
  31. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Doyle, S., Vaidya, S., O'Connell, R., Dadgostar, H., Dempsey, P., Wu, T., Rao, G., Sun, R., Haberland, M., Modlin, R., Cheng, G. Immunity (2002) [Pubmed]
  32. Nuclear localization of the Nipah virus W protein allows for inhibition of both virus- and toll-like receptor 3-triggered signaling pathways. Shaw, M.L., Cardenas, W.B., Zamarin, D., Palese, P., Basler, C.F. J. Virol. (2005) [Pubmed]
  33. TLR ligands and cytokines induce CXCR3 ligands in endothelial cells: enhanced CXCL9 in autoimmune arthritis. Loos, T., Dekeyzer, L., Struyf, S., Schutyser, E., Gijsbers, K., Gouwy, M., Fraeyman, A., Put, W., Ronsse, I., Grillet, B., Opdenakker, G., Damme, J.V., Proost, P. Lab. Invest. (2006) [Pubmed]
  34. Human keratinocytes express functional Toll-like receptor 3, 4, 5, and 9. Lebre, M.C., van der Aar, A.M., van Baarsen, L., van Capel, T.M., Schuitemaker, J.H., Kapsenberg, M.L., de Jong, E.C. J. Invest. Dermatol. (2007) [Pubmed]
  35. Toll-like receptors in cellular subsets of human tonsil T cells: altered expression during recurrent tonsillitis. Mansson, A., Adner, M., Cardell, L.O. Respir. Res. (2006) [Pubmed]
  36. Interferon regulatory factor 3 is involved in Toll-like receptor 4 (TLR4)- and TLR3-induced IL-12p35 gene activation. Goriely, S., Molle, C., Nguyen, M., Albarani, V., Haddou, N.O., Lin, R., De Wit, D., Flamand, V., Willems, F., Goldman, M. Blood (2006) [Pubmed]
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