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Gene Review

TLR2  -  toll-like receptor 2

Homo sapiens

Synonyms: CD282, TIL4, Toll-like receptor 2, Toll/interleukin-1 receptor-like protein 4
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Disease relevance of TLR2

  • These data provide a basis for understanding the innate immune response caused by leptospirosis and demonstrate a new ligand specificity for TLR2 [1].
  • Infections with Gram-negative or Gram-positive bacteria provide TLR2-specific agonists and are the major cause of severe sepsis [2].
  • In order to intervene in TLR2-driven toxemia, we raised mAb's against the extracellular domain of TLR2 [2].
  • We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes (P. acnes)-primed, LPS-induced liver damage using selective TLR ligands [3].
  • We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells [4].
  • Taken together, these results indicate that TLR2 may be an important pattern recognition receptor in the immune response directed against EBV infection [5].
  • The absence of TLR2, MyD88, and MyD88xTrif conferred both physiologic and histologic protection against sublethal ischemia at 24 h [6].
  • In this outbreak, genetic variants of TLR-2, but not TLR-4, were associated with acute reactive arthritis following infection with S enteritidis [7].
  • These data indicate that direct interaction between M. tuberculosis TLR2 ligands and CD4(+) T cells facilitated local CD4(+) T cell immune responses in patients with tuberculous pleurisy [8].

Psychiatry related information on TLR2


High impact information on TLR2

  • TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins [10].
  • Unlike responses in macrophages, the epithelial-cell response to lipoteichoic acid does not require Toll-like receptor 2 or 4 [11].
  • A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lps(d) mutation) abolishes the host immune response to lipopolysaccharide (LPS), and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and gram-positive bacteria [12].
  • The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens [13].
  • A region in the intracellular domain of TLR2 with homology to a portion of the interleukin (IL)-1 receptor that is implicated in the activation of the IL-1-receptor-associated kinase is required for this response [14].

Chemical compound and disease context of TLR2


Biological context of TLR2


Anatomical context of TLR2

  • We also show that for intact L. interrogans, it is LPS, not lipoprotein, that constitutes the predominant signaling component for macrophages through a TLR2 pathway [1].
  • METHODS: Human monocytes, human embryonic kidney cells transfected with TLR2, and peritoneal macrophages from TLR2, MyD88 knockout, and wild-type mice were studied to determine intracellular signaling and proinflammatory cytokine induction by HCV proteins [25].
  • CONCLUSIONS: HCV core and NS3 proteins trigger inflammatory pathways via TLR2 that may affect viral recognition and contribute to activation of the innate immune system [25].
  • RESULTS: Immunohistochemistry revealed a significant increase in the TLR2 and TLR4 antigen expression on submucosal cells in inflamed intestinal mucosa compared with non-inflamed mucosa [26].
  • We demonstrate that TLR2, but very little TLR4, is present on the surface of human neutrophils [15].

Associations of TLR2 with chemical compounds

  • Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism [1].
  • By systematically replacing charged aa residues by glutamine in synthetic oligopeptides, we show that the K42Q substitution leads to abrogation of TLR2 activity in both in vitro cell systems [27].
  • The removal of TLR2 lipopeptide components from LPS by phenol re-extraction substantially reduced both the IL-8 and superoxide response of the stimulated neutrophils, indicating that, unlike monocytes, the neutrophil response is preferentially directed to TLR2 ligands [15].
  • Using chromatin immunoprecipitation assays, we demonstrate that all three transcription factors interact with both endogenous and transfected TLR2 promoters after stimulation by TNF-alpha and dexamethasone [20].
  • In the presence of adenosine or A(2A)R agonists, but not A(1)R agonists, TLR2, 4, 7, and 9 agonists strongly up-regulate VEGF expression, while simultaneously down-regulating TNFalpha [28].
  • TLR2-mediated IL-1beta and TNF-alpha production by either the CD14(dim) or CD14(bright) monocytes was found to be selectively impaired in patients with AD [29].

Physical interactions of TLR2

  • Taken together, TLR1 interacts with TLR2 to recognize the lipid configuration of the native mycobacterial lipoprotein as well as several triacylated lipopeptides [30].
  • In contrast, LBP bound to NTHi did not promote any increased signaling mediated by TLR2, compared with NTHi without LBP [31].
  • The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process [32].
  • RESULTS: Regarding total IgG against PLA2, TLR2/4-binding lipopolysaccharide and TLR3-binding polyriboinosinic polyribocytidylic (PolyI:C) were the superior adjuvants for prophylactic vaccination [33].
  • 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 [34].

Enzymatic interactions of TLR2

  • Furthermore, TLR2 signalling had a potential to phosphorylate and dephosphorylate ASK1 at Ser83 residue [35].

Co-localisations of TLR2


Regulatory relationships of TLR2

  • The TLR2-mediated response to this modulin was enhanced by TLR6 but inhibited by TLR1, indicating a functional interaction between these receptors [16].
  • Excess teichoic acid, LTA-0, antibodies to phosphocholine, or antibodies to TLR4 did not inhibit the LTA-induced TLR2 stimulation [37].
  • TNF signals elicited by TLR2 agonists were blocked by the TLR-specific antibody 2392 [38].
  • Interestingly, pretreatment of HeLa cells with the p38 MAPK inhibitor SB203580 demonstrated inhibition of T. vaginalis-induced up-regulation of TLR2, 4, and 9 mRNA expression [39].
  • Coexpression of CD14 synergistically enhanced LPS signal transmission through TLR2 [40].

Other interactions of TLR2

  • Toll-like receptors (TLRs) TLR2 and TLR4 have been identified as signaling receptors activated by bacterial wall components [26].
  • GM-CSF treatment also up-regulates TLR2 and CD14 mRNA levels in neutrophils [15].
  • The lack of sensitization to TLR2 ligands by P. acnes correlated with no increase in hepatic TLR1 or TLR6 mRNA [3].
  • TLR6 associates with TLR2 and recognizes diacylated mycoplasmal lipopeptide along with TLR2 [30].
  • Accordingly, highly enriched immature LC efficiently respond to TLR2 agonists peptidoglycan and lipoteichoic acid from Gram-positive bacteria, and to dsRNA which engages TLR3 [41].

Analytical, diagnostic and therapeutic context of TLR2


  1. Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism. 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. Nat. Immunol. (2001) [Pubmed]
  2. Antagonistic antibody prevents toll-like receptor 2-driven lethal shock-like syndromes. Meng, G., Rutz, M., Schiemann, M., Metzger, J., Grabiec, A., Schwandner, R., Luppa, P.B., Ebel, F., Busch, D.H., Bauer, S., Wagner, H., Kirschning, C.J. J. Clin. Invest. (2004) [Pubmed]
  3. 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]
  4. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. Chen, K., Iribarren, P., Hu, J., Chen, J., Gong, W., Cho, E.H., Lockett, S., Dunlop, N.M., Wang, J.M. J. Biol. Chem. (2006) [Pubmed]
  5. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. Gaudreault, E., Fiola, S., Olivier, M., Gosselin, J. J. Virol. (2007) [Pubmed]
  6. TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways. Shigeoka, A.A., Holscher, T.D., King, A.J., Hall, F.W., Kiosses, W.B., Tobias, P.S., Mackman, N., McKay, D.B. J. Immunol. (2007) [Pubmed]
  7. Toll-like receptor 2 variants are associated with acute reactive arthritis. Tsui, F.W., Xi, N., Rohekar, S., Riarh, R., Bilotta, R., Tsui, H.W., Inman, R.D. Arthritis Rheum. (2008) [Pubmed]
  8. Engagement of Toll-like receptor 2 on CD4(+) T cells facilitates local immune responses in patients with tuberculous pleurisy. Chen, X., Zhang, M., Zhu, X., Deng, Q., Liu, H., Larmonier, N., Graner, M.W., Zhou, B. J. Infect. Dis. (2009) [Pubmed]
  9. Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Aliprantis, A.O., Yang, R.B., Mark, M.R., Suggett, S., Devaux, B., Radolf, J.D., Klimpel, G.R., Godowski, P., Zychlinsky, A. Science (1999) [Pubmed]
  10. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Krutzik, S.R., Ochoa, M.T., Sieling, P.A., Uematsu, S., Ng, Y.W., Legaspi, A., Liu, P.T., Cole, S.T., Godowski, P.J., Maeda, Y., Sarno, E.N., Norgard, M.V., Brennan, P.J., Akira, S., Rea, T.H., Modlin, R.L. Nat. Med. (2003) [Pubmed]
  11. Platelet-activating factor receptor and ADAM10 mediate responses to Staphylococcus aureus in epithelial cells. Lemjabbar, H., Basbaum, C. Nat. Med. (2002) [Pubmed]
  12. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Xu, Y., Tao, X., Shen, B., Horng, T., Medzhitov, R., Manley, J.L., Tong, L. Nature (2000) [Pubmed]
  13. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Underhill, D.M., Ozinsky, A., Hajjar, A.M., Stevens, A., Wilson, C.B., Bassetti, M., Aderem, A. Nature (1999) [Pubmed]
  14. Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling. Yang, R.B., Mark, M.R., Gray, A., Huang, A., Xie, M.H., Zhang, M., Goddard, A., Wood, W.I., Gurney, A.L., Godowski, P.J. Nature (1998) [Pubmed]
  15. 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]
  16. Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. Hajjar, A.M., O'Mahony, D.S., Ozinsky, A., Underhill, D.M., Aderem, A., Klebanoff, S.J., Wilson, C.B. J. Immunol. (2001) [Pubmed]
  17. Toll-like receptor signaling in anti-cancer immunity. Okamoto, M., Sato, M. J. Med. Invest. (2003) [Pubmed]
  18. 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]
  19. Upregulation of toll-like receptor 2 gene expression in macrophage response to peptidoglycan and high concentration of lipopolysaccharide is involved in NF-kappa b activation. Liu, Y., Wang, Y., Yamakuchi, M., Isowaki, S., Nagata, E., Kanmura, Y., Kitajima, I., Maruyama, I. Infect. Immun. (2001) [Pubmed]
  20. Glucocorticoids and tumor necrosis factor alpha cooperatively regulate toll-like receptor 2 gene expression. Hermoso, M.A., Matsuguchi, T., Smoak, K., Cidlowski, J.A. Mol. Cell. Biol. (2004) [Pubmed]
  21. Selective roles for Toll-like receptor (TLR)2 and TLR4 in the regulation of neutrophil activation and life span. Sabroe, I., Prince, L.R., Jones, E.C., Horsburgh, M.J., Foster, S.J., Vogel, S.N., Dower, S.K., Whyte, M.K. J. Immunol. (2003) [Pubmed]
  22. Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. Kim, J., Ochoa, M.T., Krutzik, S.R., Takeuchi, O., Uematsu, S., Legaspi, A.J., Brightbill, H.D., Holland, D., Cunliffe, W.J., Akira, S., Sieling, P.A., Godowski, P.J., Modlin, R.L. J. Immunol. (2002) [Pubmed]
  23. The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. Yoshida, H., Jono, H., Kai, H., Li, J.D. J. Biol. Chem. (2005) [Pubmed]
  24. 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]
  25. Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Dolganiuc, A., Oak, S., Kodys, K., Golenbock, D.T., Finberg, R.W., Kurt-Jones, E., Szabo, G. Gastroenterology (2004) [Pubmed]
  26. 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]
  27. A hypervariable N-terminal region of Yersinia LcrV determines Toll-like receptor 2-mediated IL-10 induction and mouse virulence. Sing, A., Reithmeier-Rost, D., Granfors, K., Hill, J., Roggenkamp, A., Heesemann, J. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  28. 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]
  29. Selective impairment of Toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis. Hasannejad, H., Takahashi, R., Kimishima, M., Hayakawa, K., Shiohara, T. J. Allergy Clin. Immunol. (2007) [Pubmed]
  30. Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R.L., Akira, S. J. Immunol. (2002) [Pubmed]
  31. 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]
  32. Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. Netea, M.G., Ferwerda, G., de Jong, D.J., Jansen, T., Jacobs, L., Kramer, M., Naber, T.H., Drenth, J.P., Girardin, S.E., Kullberg, B.J., Adema, G.J., Van der Meer, J.W. J. Immunol. (2005) [Pubmed]
  33. Toll-like receptor ligands as adjuvants in allergen-specific immunotherapy. Johansen, P., Senti, G., Martinez Gomez, J.M., Storni, T., von Beust, B.R., Wüthrich, B., Bot, A., Kündig, T.M. Clin. Exp. Allergy (2005) [Pubmed]
  34. 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]
  35. Apoptosis signal-regulating kinase 1-mediated sustained p38 mitogen-activated protein kinase activation regulates mycoplasmal lipoprotein- and staphylococcal peptidoglycan-triggered Toll-like receptor 2 signalling pathways. Into, T., Shibata, K. Cell. Microbiol. (2005) [Pubmed]
  36. Surface-expressed TLR6 participates in the recognition of diacylated lipopeptide and peptidoglycan in human cells. Nakao, Y., Funami, K., Kikkawa, S., Taniguchi, M., Nishiguchi, M., Fukumori, Y., Seya, T., Matsumoto, M. J. Immunol. (2005) [Pubmed]
  37. 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]
  38. Human monocytoid cells as a model to study Toll-like receptor-mediated activation. Remer, K.A., Brcic, M., Sauter, K.S., Jungi, T.W. J. Immunol. Methods (2006) [Pubmed]
  39. Dependence on p38 MAPK signalling in the up-regulation of TLR2, TLR4 and TLR9 gene expression in Trichomonas vaginalis-treated HeLa cells. Chang, J.H., Park, J.Y., Kim, S.K. Immunology (2006) [Pubmed]
  40. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. Kirschning, C.J., Wesche, H., Merrill Ayres, T., Rothe, M. J. Exp. Med. (1998) [Pubmed]
  41. 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]
  42. 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]
  43. Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. Melmed, G., Thomas, L.S., Lee, N., Tesfay, S.Y., Lukasek, K., Michelsen, K.S., Zhou, Y., Hu, B., Arditi, M., Abreu, M.T. J. Immunol. (2003) [Pubmed]
  44. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. Schwandner, R., Dziarski, R., Wesche, H., Rothe, M., Kirschning, C.J. J. Biol. Chem. (1999) [Pubmed]
  45. Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Seibl, R., Birchler, T., Loeliger, S., Hossle, J.P., Gay, R.E., Saurenmann, T., Michel, B.A., Seger, R.A., Gay, S., Lauener, R.P. Am. J. Pathol. (2003) [Pubmed]
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