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Gene Review

TLR9  -  toll-like receptor 9

Homo sapiens

Synonyms: CD289, Toll-like receptor 9, UNQ5798/PRO19605
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Disease relevance of TLR9


Psychiatry related information on TLR9

  • CONCLUSIONS: The presence of functional TLR9 in LSECs emphasizes the importance of these cells in the innate defense mechanisms of the liver [5].

High impact information on TLR9

  • IPCs display plasma cell morphology, selectively express Toll-like receptor (TLR)-7 and TLR9, and are specialized in rapidly secreting massive amounts of type 1 interferon following viral stimulation [6].
  • Injection into mice of immunostimulatory siRNA, when complexed with cationic liposomes, induced systemic immune responses in the same range as the TLR9 ligand CpG, including IFN-alpha in serum and activation of T cells and dendritic cells in spleen [7].
  • TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells [8].
  • These findings reveal opposing inflammatory and regulatory roles for TLR7 and TLR9, despite similar tissue expression and signaling pathways [9].
  • Toll-like Receptor 7 and TLR9 Dictate Autoantibody Specificity and Have Opposing Inflammatory and Regulatory Roles in a Murine Model of Lupus [9].

Chemical compound and disease context of TLR9


Biological context of TLR9


Anatomical context of TLR9


Associations of TLR9 with chemical compounds

  • However, TLR8 activation by R-848 and TLR2 activation by [S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-R-Cys-S-Ser-Lys4-OH, trihydrochloride)] were not inhibited by chloroquine, whereas TLR9 activation by CpG oligodeoxynucleotides was abolished [24].
  • Unmethlylated CpG dinucleotides induce a strong T-helper-1-like inflammatory response, presumably mediated by Toll-like receptor 9 (TLR9) [18].
  • In addition, we found that TLR9 expression at the surface of PBMC was up-regulated approximately fourfold following stimulation with the gram-negative bacterial cell wall component lipopolysaccharide, suggesting a potential modulatory role of TLR4 agonists on TLR9 expression [18].
  • In some cases cells were pretreated with chloroquine, an inhibitor of TLR-9 signaling, or SB202190, an inhibitor of the mitogen activated protein kinase p38, prior to treatment with IL-1beta and CpG [25].
  • This suggests that the human epithelium is able to avoid inappropriate immune responses to luminal bacterial products through modulation of the TLR9 pathway [26].
  • Alignment of bases to PD 2' deoxyribose enhanced its TLR9 agonistic function, while only CpG-motifs introduced to inhibitory PS 2' deoxyribose converted the antagonistic activity into powerful agonistic function [27].

Regulatory relationships of TLR9

  • Surprisingly, the TLR9 ligand CpG oligodeoxynucleotide 2006 was able to specifically inhibit poly(I:C)-induced IL-8 and IDO expression [28].
  • In this study, we demonstrate that HMGB1 suppresses PDC cytokine secretion and maturation in response to TLR9 agonists including the hypomethylated oligodeoxynucleotide CpG- and DNA-containing viruses [29].
  • Heat shock activated ERK and NF-kappaB signal pathways, and pretreatment of B cells with specific inhibitors of ERK or NF-kappaB signal pathways inhibited heat shock-induced up-regulation of TLR9 expression [30].
  • In contrast, TLR9 ligand-induced IFN-beta production, which is MyD88-dependent, was tolerized by prior TLR stimulation [31].
  • Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process [32].

Other interactions of TLR9

  • Triad3A overexpression promoted substantial degradation of TLR4 and TLR9 with a concomitant decrease in signaling, but did not affect TLR2 expression or signaling [33].
  • Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increased TLR2 and TLR9 expression levels [34].
  • The other TLRs that are evolutionarily closely related and highly homologous are TLR7, TLR8, and TLR9 [35].
  • Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules [36].
  • Collectively, these findings suggest a synergistic role of the TLR9/CD40 system and a critical role for the immunomodulatory cytokine IL-10 in the orchestration of CpG-ODN-induced responses in B lymphocytes [37].

Analytical, diagnostic and therapeutic context of TLR9


  1. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. Lund, J., Sato, A., Akira, S., Medzhitov, R., Iwasaki, A. J. Exp. Med. (2003) [Pubmed]
  2. HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. Wille-Reece, U., Flynn, B.J., Loré, K., Koup, R.A., Kedl, R.M., Mattapallil, J.J., Weiss, W.R., Roederer, M., Seder, R.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  3. 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]
  4. Signaling danger: toll-like receptors and their potential roles in kidney disease. Anders, H.J., Banas, B., Schlöndorff, D. J. Am. Soc. Nephrol. (2004) [Pubmed]
  5. Toll-like receptor 9 (TLR9) is present in murine liver sinusoidal endothelial cells (LSECs) and mediates the effect of CpG-oligonucleotides. Martin-Armas, M., Simon-Santamaria, J., Pettersen, I., Moens, U., Smedsrød, B., Sveinbjørnsson, B. J. Hepatol. (2006) [Pubmed]
  6. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Liu, Y.J. Annu. Rev. Immunol. (2005) [Pubmed]
  7. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Hornung, V., Guenthner-Biller, M., Bourquin, C., Ablasser, A., Schlee, M., Uematsu, S., Noronha, A., Manoharan, M., Akira, S., de Fougerolles, A., Endres, S., Hartmann, G. Nat. Med. (2005) [Pubmed]
  8. A Toll-like receptor recognizes bacterial DNA. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., Akira, S. Nature (2000) [Pubmed]
  9. Toll-like Receptor 7 and TLR9 Dictate Autoantibody Specificity and Have Opposing Inflammatory and Regulatory Roles in a Murine Model of Lupus. Christensen, S.R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R.A., Shlomchik, M.J. Immunity (2006) [Pubmed]
  10. Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors. Damiano, V., Caputo, R., Bianco, R., D'Armiento, F.P., Leonardi, A., De Placido, S., Bianco, A.R., Agrawal, S., Ciardiello, F., Tortora, G. Clin. Cancer Res. (2006) [Pubmed]
  11. Toll-like receptor 9 binds single-stranded CpG-DNA in a sequence- and pH-dependent manner. Rutz, M., Metzger, J., Gellert, T., Luppa, P., Lipford, G.B., Wagner, H., Bauer, S. Eur. J. Immunol. (2004) [Pubmed]
  12. Critical role of Toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury. Velayudham, A., Hritz, I., Dolganiuc, A., Mandrekar, P., Kurt-Jones, E., Szabo, G. J. Hepatol. (2006) [Pubmed]
  13. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Ahmad-Nejad, P., Häcker, H., Rutz, M., Bauer, S., Vabulas, R.M., Wagner, H. Eur. J. Immunol. (2002) [Pubmed]
  14. TLR9-based immunotherapy for allergic disease. Hayashi, T., Raz, E. Am. J. Med. (2006) [Pubmed]
  15. Collaborative Action of NF-{kappa}B and p38 MAPK Is Involved in CpG DNA-Induced IFN-{alpha} and Chemokine Production in Human Plasmacytoid Dendritic Cells. Osawa, Y., Iho, S., Takauji, R., Takatsuka, H., Yamamoto, S., Takahashi, T., Horiguchi, S., Urasaki, Y., Matsuki, T., Fujieda, S. J. Immunol. (2006) [Pubmed]
  16. Toll-like receptor 2 (TLR2) and TLR9 signaling results in HIV-long terminal repeat trans-activation and HIV replication in HIV-1 transgenic mouse spleen cells: implications of simultaneous activation of TLRs on HIV replication. Equils, O., Schito, M.L., Karahashi, H., Madak, Z., Yarali, A., Michelsen, K.S., Sher, A., Arditi, M. J. Immunol. (2003) [Pubmed]
  17. Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Jego, G., Bataille, R., Geffroy-Luseau, A., Descamps, G., Pellat-Deceunynck, C. Leukemia (2006) [Pubmed]
  18. Toll-like receptor 9 can be expressed at the cell surface of distinct populations of tonsils and human peripheral blood mononuclear cells. Eaton-Bassiri, A., Dillon, S.B., Cunningham, M., Rycyzyn, M.A., Mills, J., Sarisky, R.T., Mbow, M.L. Infect. Immun. (2004) [Pubmed]
  19. Toll-like receptors induce a phagocytic gene program through p38. Doyle, S.E., O'Connell, R.M., Miranda, G.A., Vaidya, S.A., Chow, E.K., Liu, P.T., Suzuki, S., Suzuki, N., Modlin, R.L., Yeh, W.C., Lane, T.F., Cheng, G. J. Exp. Med. (2004) [Pubmed]
  20. IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. Sirén, J., Pirhonen, J., Julkunen, I., Matikainen, S. J. Immunol. (2005) [Pubmed]
  21. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. Hornung, V., Rothenfusser, S., Britsch, S., Krug, A., Jahrsdörfer, B., Giese, T., Endres, S., Hartmann, G. J. Immunol. (2002) [Pubmed]
  22. Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn's disease. van Heel, D.A., Ghosh, S., Hunt, K.A., Mathew, C.G., Forbes, A., Jewell, D.P., Playford, R.J. Gut (2005) [Pubmed]
  23. Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells. Kim, S., McAuliffe, W.J., Zaritskaya, L.S., Moore, P.A., Zhang, L., Nardelli, B. Infect. Immun. (2004) [Pubmed]
  24. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Lee, J., Chuang, T.H., Redecke, V., She, L., Pitha, P.M., Carson, D.A., Raz, E., Cottam, H.B. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  25. CpG DNA modulates interleukin 1beta-induced interleukin-8 expression in human bronchial epithelial (16HBE14o-) cells. Parilla, N.W., Hughes, V.S., Lierl, K.M., Wong, H.R., Page, K. Respir. Res. (2006) [Pubmed]
  26. Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium. Pedersen, G., Andresen, L., Matthiessen, M.W., Rask-Madsen, J., Brynskov, J. Clin. Exp. Immunol. (2005) [Pubmed]
  27. The sweetness of the DNA backbone drives Toll-like receptor 9. Wagner, H. Curr. Opin. Immunol. (2008) [Pubmed]
  28. IL-8 and IDO Expression by Human Gingival Fibroblasts via TLRs. Mahanonda, R., Sa-Ard-Iam, N., Montreekachon, P., Pimkhaokham, A., Yongvanichit, K., Fukuda, M.M., Pichyangkul, S. J. Immunol. (2007) [Pubmed]
  29. High Mobility Group B1 Protein Suppresses the Human Plasmacytoid Dendritic Cell Response to TLR9 Agonists. Popovic, P.J., Demarco, R., Lotze, M.T., Winikoff, S.E., Bartlett, D.L., Krieg, A.M., Guo, Z.S., Brown, C.K., Tracey, K.J., Zeh, H.J. J. Immunol. (2006) [Pubmed]
  30. Heat shock up-regulates TLR9 expression in human B cells through activation of ERK and NF-kappaB signal pathways. Chen, W., Wang, J., An, H., Zhou, J., Zhang, L., Cao, X. Immunol. Lett. (2005) [Pubmed]
  31. Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Broad, A., Kirby, J.A., Jones, D.E. Immunology (2007) [Pubmed]
  32. Expansion of toll-like receptor 9-expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process. Papadimitraki, E.D., Choulaki, C., Koutala, E., Bertsias, G., Tsatsanis, C., Gergianaki, I., Raptopoulou, A., Kritikos, H.D., Mamalaki, C., Sidiropoulos, P., Boumpas, D.T. Arthritis Rheum. (2006) [Pubmed]
  33. Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Chuang, T.H., Ulevitch, R.J. Nat. Immunol. (2004) [Pubmed]
  34. Toll-like receptors stimulate human neutrophil function. Hayashi, F., Means, T.K., Luster, A.D. Blood (2003) [Pubmed]
  35. The Functional Effects of Physical Interactions among Toll-like Receptors 7, 8, and 9. Wang, J., Shao, Y., Bennett, T.A., Shankar, R.A., Wightman, P.D., Reddy, L.G. J. Biol. Chem. (2006) [Pubmed]
  36. Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. Liu, S., Gallo, D.J., Green, A.M., Williams, D.L., Gong, X., Shapiro, R.A., Gambotto, A.A., Humphris, E.L., Vodovotz, Y., Billiar, T.R. Infect. Immun. (2002) [Pubmed]
  37. CD40-dependent and -independent activation of human tonsil B cells by CpG oligodeoxynucleotides. Gantner, F., Hermann, P., Nakashima, K., Matsukawa, S., Sakai, K., Bacon, K.B. Eur. J. Immunol. (2003) [Pubmed]
  38. Immunomodulatory oligonucleotides containing a cytosine-phosphate-2'-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists. Kandimalla, E.R., Bhagat, L., Li, Y., Yu, D., Wang, D., Cong, Y.P., Song, S.S., Tang, J.X., Sullivan, T., Agrawal, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  39. Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses. Kirschning, C.J., Bauer, S. Int. J. Med. Microbiol. (2001) [Pubmed]
  40. Bacterial DNA activates human neutrophils by a CpG-independent pathway. Trevani, A.S., Chorny, A., Salamone, G., Vermeulen, M., Gamberale, R., Schettini, J., Raiden, S., Geffner, J. Eur. J. Immunol. (2003) [Pubmed]
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