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Gene Review

TLR4  -  toll-like receptor 4

Homo sapiens

Synonyms: ARMD10, CD284, TLR-4, TOLL, Toll-like receptor 4, ...
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Disease relevance of TLR4


Psychiatry related information on TLR4

  • Therefore, the purpose of this study was to determine the association between age, physical activity status, biomarkers of inflammation, and TLR4 [9].
  • To investigate the role of TLR4 in the amyloidogenesis in vivo, we determined the amounts of cerebral Abeta in Alzheimer's disease mouse models with different genotypes of TLR4 using three distinct methods [10].

High impact information on TLR4

  • Beta-defensins interact with CCR6; murine beta-defensin-2 in addition activates TLR4 [11].
  • TLR4 belongs to a family of innate immunity receptors that possess a large extracellular domain of leucine-rich repeats, a single trans-membrane segment, and a smaller cytoplasmic signaling region that engages the adaptor protein MyD88 [12].
  • Most significant has been the identification of the plasma membrane protein TLR4 as the lipid A signaling receptor of animal cells [12].
  • This binding recruits a key adaptor MyD88 to TLR4, suggesting that there is crosstalk between the TLR signaling pathway and phospholipid metabolism [13].
  • TIRAP then functions to facilitate MyD88 delivery to activated TLR4 to initiate signal transduction [14].

Chemical compound and disease context of TLR4


Biological context of TLR4


Anatomical context of TLR4


Associations of TLR4 with chemical compounds


Physical interactions of TLR4

  • MD-2 must be bound to TLR4 on the cell surface before binding can occur [35].
  • Our findings implicate Btk as a Toll/interleukin-1 receptor domain-binding protein that is important for NFkappaB activation by TLR4 [36].
  • These results suggest that TLR4 receptor complex is the molecular target of curcumin in addition to IKKbeta [37].
  • This was supported by decreased IRAK-1:TRAF6 association in TLR4 induced but sustained presence of IRAK-1:TRAF6 complexes in TLR2- plus TLR4-stimulated monocytes after alcohol treatment [38].
  • Rapid recycling of TLR4/CD14/MD-2 complexes between the Golgi and the plasma membrane was a prominent phenomenon [39].

Co-localisations of TLR4


Regulatory relationships of TLR4

  • Toll-like receptor (TLR)2 and TLR4 agonists regulate CCR expression in human monocytic cells [42].
  • Excess teichoic acid, LTA-0, antibodies to phosphocholine, or antibodies to TLR4 did not inhibit the LTA-induced TLR2 stimulation [43].
  • Inhibition was specific for TLR1 because TL5 failed to block TLR4 function [44].
  • These data suggest that, upon NTHi infection, low numbers of bacteria binding LBP may activate TLR4-bearing cells, such as alveolar macrophages, and consequently induce an inflammatory response [45].
  • These findings suggest that CXCR4 could exert local control of TLR4 and suggest the possibility of new therapeutic approaches to suppression of TLR4 function [46].
  • Single mutants K122A and K132A each react with E.CD14 +/- TLR4 and promote TLR4-dependent cell activation by endotoxin suggesting that Phe(121) and Tyr(131) are needed for TLR4-independent transfer of endotoxin from CD14 to MD-2 and also needed for TLR4 activation by bound E.MD-2 [47].

Other interactions of TLR4


Analytical, diagnostic and therapeutic context of TLR4


  1. Role of toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils. Kurt-Jones, E.A., Mandell, L., Whitney, C., Padgett, A., Gosselin, K., Newburger, P.E., Finberg, R.W. Blood (2002) [Pubmed]
  2. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Aslam, R., Speck, E.R., Kim, M., Crow, A.R., Bang, K.W., Nestel, F.P., Ni, H., Lazarus, A.H., Freedman, J., Semple, J.W. Blood (2006) [Pubmed]
  3. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Chen, Y.C., Giovannucci, E., Lazarus, R., Kraft, P., Ketkar, S., Hunter, D.J. Cancer Res. (2005) [Pubmed]
  4. Selective priming to Toll-like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up-regulation of MD-2 in mice. Romics, L., Dolganiuc, A., Kodys, K., Drechsler, Y., Oak, S., Velayudham, A., Mandrekar, P., Szabo, G. Hepatology (2004) [Pubmed]
  5. Response to Neisseria gonorrhoeae by cervicovaginal epithelial cells occurs in the absence of toll-like receptor 4-mediated signaling. Fichorova, R.N., Cronin, A.O., Lien, E., Anderson, D.J., Ingalls, R.R. J. Immunol. (2002) [Pubmed]
  6. Reduced toll-like receptor 4 expression in children with asymptomatic bacteriuria. Ragnarsdóttir, B., Samuelsson, M., Gustafsson, M.C., Leijonhufvud, I., Karpman, D., Svanborg, C. J. Infect. Dis. (2007) [Pubmed]
  7. Toll-like receptors and chondrocytes: the lipopolysaccharide-induced decrease in cartilage matrix synthesis is dependent on the presence of toll-like receptor 4 and antagonized by bone morphogenetic protein 7. Bobacz, K., Sunk, I.G., Hofstaetter, J.G., Amoyo, L., Toma, C.D., Akira, S., Weichhart, T., Saemann, M., Smolen, J.S. Arthritis Rheum. (2007) [Pubmed]
  8. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Clark, S.R., Ma, A.C., Tavener, S.A., McDonald, B., Goodarzi, Z., Kelly, M.M., Patel, K.D., Chakrabarti, S., McAvoy, E., Sinclair, G.D., Keys, E.M., Allen-Vercoe, E., Devinney, R., Doig, C.J., Green, F.H., Kubes, P. Nat. Med. (2007) [Pubmed]
  9. Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. McFarlin, B.K., Flynn, M.G., Campbell, W.W., Craig, B.A., Robinson, J.P., Stewart, L.K., Timmerman, K.L., Coen, P.M. J. Gerontol. A Biol. Sci. Med. Sci. (2006) [Pubmed]
  10. Role of toll-like receptor signalling in Abeta uptake and clearance. Tahara, K., Kim, H.D., Jin, J.J., Maxwell, J.A., Li, L., Fukuchi, K. Brain (2006) [Pubmed]
  11. Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Yang, D., Biragyn, A., Hoover, D.M., Lubkowski, J., Oppenheim, J.J. Annu. Rev. Immunol. (2004) [Pubmed]
  12. Lipopolysaccharide endotoxins. Raetz, C.R., Whitfield, C. Annu. Rev. Biochem. (2002) [Pubmed]
  13. Sorting out Toll signals. Fitzgerald, K.A., Chen, Z.J. Cell (2006) [Pubmed]
  14. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Kagan, J.C., Medzhitov, R. Cell (2006) [Pubmed]
  15. Heterozygous Thr 135 Ala polymorphism at leucine-rich repeat (LRR) in genomic DNA of toll-like receptor 4 in patients with poorly-differentiated gastric adenocarcinomas. Ohara, T., Morishita, T., Suzuki, H., Hibi, T. Int. J. Mol. Med. (2006) [Pubmed]
  16. Toll-like receptor signaling in anti-cancer immunity. Okamoto, M., Sato, M. J. Med. Invest. (2003) [Pubmed]
  17. Tumor necrosis factor alpha blockade treatment down-modulates the increased systemic and local expression of Toll-like receptor 2 and Toll-like receptor 4 in spondylarthropathy. De Rycke, L., Vandooren, B., Kruithof, E., De Keyser, F., Veys, E.M., Baeten, D. Arthritis Rheum. (2005) [Pubmed]
  18. The polysaccharide portion plays an indispensable role in Salmonella lipopolysaccharide-induced activation of NF-kappaB through human toll-like receptor 4. Muroi, M., Tanamoto, K. Infect. Immun. (2002) [Pubmed]
  19. Sensitization of human aortic endothelial cells to lipopolysaccharide via regulation of Toll-like receptor 4 by bacterial fimbria-dependent invasion. Yumoto, H., Chou, H.H., Takahashi, Y., Davey, M., Gibson, F.C., Genco, C.A. Infect. Immun. (2005) [Pubmed]
  20. Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism. Säemann, M.D., Weichhart, T., Zeyda, M., Staffler, G., Schunn, M., Stuhlmeier, K.M., Sobanov, Y., Stulnig, T.M., Akira, S., von Gabain, A., von Ahsen, U., Hörl, W.H., Zlabinger, G.J. J. Clin. Invest. (2005) [Pubmed]
  21. Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide. Bosisio, D., Polentarutti, N., Sironi, M., Bernasconi, S., Miyake, K., Webb, G.R., Martin, M.U., Mantovani, A., Muzio, M. Blood (2002) [Pubmed]
  22. Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Paik, Y.H., Schwabe, R.F., Bataller, R., Russo, M.P., Jobin, C., Brenner, D.A. Hepatology (2003) [Pubmed]
  23. TIRAP: an adapter molecule in the Toll signaling pathway. Horng, T., Barton, G.M., Medzhitov, R. Nat. Immunol. (2001) [Pubmed]
  24. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Divanovic, S., Trompette, A., Atabani, S.F., Madan, R., Golenbock, D.T., Visintin, A., Finberg, R.W., Tarakhovsky, A., Vogel, S.N., Belkaid, Y., Kurt-Jones, E.A., Karp, C.L. Nat. Immunol. (2005) [Pubmed]
  25. 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]
  26. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Nencioni, A., Schwarzenberg, K., Brauer, K.M., Schmidt, S.M., Ballestrero, A., Grünebach, F., Brossart, P. Blood (2006) [Pubmed]
  27. TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells. Abreu, M.T., Arnold, E.T., Thomas, L.S., Gonsky, R., Zhou, Y., Hu, B., Arditi, M. J. Biol. Chem. (2002) [Pubmed]
  28. A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4. Kennedy, M.N., Mullen, G.E., Leifer, C.A., Lee, C., Mazzoni, A., Dileepan, K.N., Segal, D.M. J. Biol. Chem. (2004) [Pubmed]
  29. Regions of the mouse CD14 molecule required for toll-like receptor 2- and 4-mediated activation of NF-kappa B. Muroi, M., Ohnishi, T., Tanamoto, K. J. Biol. Chem. (2002) [Pubmed]
  30. A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair. Leaphart, C.L., Cavallo, J., Gribar, S.C., Cetin, S., Li, J., Branca, M.F., Dubowski, T.D., Sodhi, C.P., Hackam, D.J. J. Immunol. (2007) [Pubmed]
  31. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. Rallabhandi, P., Nhu, Q.M., Toshchakov, V.Y., Piao, W., Medvedev, A.E., Hollenberg, M.D., Fasano, A., Vogel, S.N. J. Biol. Chem. (2008) [Pubmed]
  32. Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. Devaraj, S., Dasu, M.R., Rockwood, J., Winter, W., Griffen, S.C., Jialal, I. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  33. HIV-1 Tat protein suppresses cholangiocyte toll-like receptor 4 expression and defense against Cryptosporidium parvum. O'Hara, S.P., Small, A.J., Gajdos, G.B., Badley, A.D., Chen, X.M., Larusso, N.F. J. Infect. Dis. (2009) [Pubmed]
  34. Essential roles of hydrophobic residues in both MD-2 and toll-like receptor 4 in activation by endotoxin. Resman, N., Vasl, J., Oblak, A., Pristovsek, P., Gioannini, T.L., Weiss, J.P., Jerala, R. J. Biol. Chem. (2009) [Pubmed]
  35. Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction. Visintin, A., Latz, E., Monks, B.G., Espevik, T., Golenbock, D.T. J. Biol. Chem. (2003) [Pubmed]
  36. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. Jefferies, C.A., Doyle, S., Brunner, C., Dunne, A., Brint, E., Wietek, C., Walch, E., Wirth, T., O'Neill, L.A. J. Biol. Chem. (2003) [Pubmed]
  37. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Youn, H.S., Saitoh, S.I., Miyake, K., Hwang, D.H. Biochem. Pharmacol. (2006) [Pubmed]
  38. TLR2- and TLR4-mediated signals determine attenuation or augmentation of inflammation by acute alcohol in monocytes. Oak, S., Mandrekar, P., Catalano, D., Kodys, K., Szabo, G. J. Immunol. (2006) [Pubmed]
  39. Cell distributions and functions of Toll-like receptor 4 studied by fluorescent gene constructs. Espevik, T., Latz, E., Lien, E., Monks, B., Golenbock, D.T. Scand. J. Infect. Dis. (2003) [Pubmed]
  40. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. Schromm, A.B., Lien, E., Henneke, P., Chow, J.C., Yoshimura, A., Heine, H., Latz, E., Monks, B.G., Schwartz, D.A., Miyake, K., Golenbock, D.T. J. Exp. Med. (2001) [Pubmed]
  41. Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity. Husebye, H., Halaas, Ø., Stenmark, H., Tunheim, G., Sandanger, Ø., Bogen, B., Brech, A., Latz, E., Espevik, T. EMBO J. (2006) [Pubmed]
  42. Toll-like receptor (TLR)2 and TLR4 agonists regulate CCR expression in human monocytic cells. Parker, L.C., Whyte, M.K., Vogel, S.N., Dower, S.K., Sabroe, I. J. Immunol. (2004) [Pubmed]
  43. Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating Toll-like receptor 2. Han, S.H., Kim, J.H., Martin, M., Michalek, S.M., Nahm, M.H. Infect. Immun. (2003) [Pubmed]
  44. Toll-like receptor 1 inhibits Toll-like receptor 4 signaling in endothelial cells. Spitzer, J.H., Visintin, A., Mazzoni, A., Kennedy, M.N., Segal, D.M. Eur. J. Immunol. (2002) [Pubmed]
  45. Lipopolysaccharide-binding protein increases toll-like receptor 4-dependent activation by nontypeable Haemophilus influenzae. Lazou Ahrén, I., Bjartell, A., Egesten, A., Riesbeck, K. J. Infect. Dis. (2001) [Pubmed]
  46. Selective suppression of Toll-like receptor 4 activation by chemokine receptor 4. Kishore, S.P., Bungum, M.K., Platt, J.L., Brunn, G.J. FEBS Lett. (2005) [Pubmed]
  47. Novel roles in human MD-2 of phenylalanines 121 and 126 and tyrosine 131 in activation of Toll-like receptor 4 by endotoxin. Teghanemt, A., Re, F., Prohinar, P., Widstrom, R., Gioannini, T.L., Weiss, J.P. J. Biol. Chem. (2008) [Pubmed]
  48. 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]
  49. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. Häcker, H., Vabulas, R.M., Takeuchi, O., Hoshino, K., Akira, S., Wagner, H. J. Exp. Med. (2000) [Pubmed]
  50. The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Bourke, E., Bosisio, D., Golay, J., Polentarutti, N., Mantovani, A. Blood (2003) [Pubmed]
  51. Toll-like receptor 4 mediates intracellular signaling without TNF-alpha release in response to Cryptococcus neoformans polysaccharide capsule. Shoham, S., Huang, C., Chen, J.M., Golenbock, D.T., Levitz, S.M. J. Immunol. (2001) [Pubmed]
  52. Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. Lee, J.Y., Zhao, L., Youn, H.S., Weatherill, A.R., Tapping, R., Feng, L., Lee, W.H., Fitzgerald, K.A., Hwang, D.H. J. Biol. Chem. (2004) [Pubmed]
  53. Response of human pulmonary epithelial cells to lipopolysaccharide involves Toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. Guillot, L., Medjane, S., Le-Barillec, K., Balloy, V., Danel, C., Chignard, M., Si-Tahar, M. J. Biol. Chem. (2004) [Pubmed]
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