Toll-like receptor signalling

Nature Reviews Immunology

Volumn 4, Issue 7, 2004, Pages 499-511

  Akira, Shizuo ^a   Takeda, Kiyoshi ^b  

^a OSAKA UNIVERSITY   (Japan)

^b KYUSHU UNIVERSITY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

TOLL LIKE RECEPTOR;

ANTIGEN RECOGNITION; ANTIGEN SPECIFICITY; GENE EXPRESSION; IMMUNE SYSTEM; IMMUNOBIOLOGY; MICROBIAL IMMUNITY; MOLECULAR BIOLOGY; NONHUMAN; PRIORITY JOURNAL; REVIEW;

EID: 3142724031     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri1391     Document Type: Review

References (144)

1. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197-216 (2002).
2. Beutler, B. & Rietschel, E. T. Innate immune sensing and its roots: the story of endotoxin. Nature Rev. Immunol. 3, 169-176 (2003).
3. Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135-145 (2001).
4. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675-680 (2001).
5. Hashimoto, C., Hudson, K. L. & Anderson, K. V. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 52, 269-279 (1988).
6. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.-M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973-983 (1996).
7. Slack, J. L. et al. Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J. Biol. Chem. 275, 4670-4678 (2000).
8. Xu, Y. et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408, 111-115 (2000).
9. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085-2088 (1998). The first report that TLR4 is involved in the recognition of bacterial components.
10. Bell, J. K. et al. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol. 24, 528-533 (2003).
11. Ahmad-Nejad, P. et al. Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur. J. Immunol. 32, 1958-1968 (2002).
12. Heil, F. et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur. J. Immunol. 33, 2987-2997 (2003).
13. Matsumoto, M. et al. Subcellular localization of Toll-like receptor 3 in human dendritic cells. J. Immunol. 171, 3154-3162 (2003).
14. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nature Immunol. 5, 190-198 (2004).
15. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335-376 (2003).
16. Dunne, A. & O'Neill, L. A. The interleukin-1 receptor/Toll-like receptor superfamily: signal transduction during inflammation and host defense. Sci. STKE [online], 2003, re3 (2003).
17. Lord, K. A., Hoffman-Liebermann, B. & Liebermann, D. A. Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6. Oncogene 5, 1095-1097 (1990).
18. Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK ((Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278, 1612-1615 (1997).
19. Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837-847 (1997).
20. Burns, K. et al. MyD88, an adapter protein involved in interleukin-1 signaling. J. Biol. Chem. 273, 12203-12209 (1998).
21. Dunne, A., Ejdeback, M., Ludidi, P. L., O'Neill, L. A. & Gay, N. J. Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88. J. Biol. Chem. 278, 41443-41451 (2003).
22. Janssens, S. & Beyaert, R. Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol. Cell 11, 293-302 (2003). A review of the functional roles of the IRAK family.
23. Li, X. et al. Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor associated kinase. Mol. Cell. Biol. 19, 4643-4652 (1999).
24. Li, S., Strelow, A., Fontana, E. J. & Wesche, H. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc. Natl Acad. Sci. USA 99, 5567-5572 (2002).
25. Kanakaraj, P. et al. Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice. J. Exp. Med. 187, 2073-2079 (1998).
26. Thomas, J. A. et al. Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J. Immunol. 163, 978-984 (1999).
27. Swantek, J. L., Tsen, M. F., Cobb, M. H. & Thomas, J. A. IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. J. Immunol. 164, 4301-4306 (2000).
28. Suzuki, N. et al. Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416, 750-756 (2002).
29. Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076-2079 (2003).
30. Bradley, J. R. & Pober, J. S. Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20, 6482-6491 (2001).
31. Ye, H. et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418, 443-447 (2002).
32. Yamaguchi, K. et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science 270, 2008-2011 (1995).
33. Takaesu, G. et al. TAK1 is critical for IκB kinase-mediated activation of the NF-κB pathway. J. Mol. Biol. 326, 105-115 (2003).
34. Shibuya, H. et al. TAB1: an activator of the TAK1 MAPKKK in TGF-β signal transduction. Science 272, 1179-1182 (1996).
35. Takaesu, G. et al. TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol. Cell 5, 649-658 (2000).
36. Sanjo, H. et al. TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Mol. Cell. Biol. 23, 1231-1238 (2003).
37. Ishitani, T. et al. Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling. EMBO J. 22, 6277-6288 (2003).
38. Deng, L. et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103, 351-361 (2000).
39. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-351 (2001).
40. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621-663 (2000).
41. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495-1499 (2001).
42. Dejardin, E. et al. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525-535 (2002).
43. Amir, R. E., Haecker, H., Karin, M. & Ciechanover, A. Mechanism of processing of the NF-κB2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of NEDD8-modification on the SCF (β-TrCP) ubiquitin ligase. Oncogene 23, 2540-2547 (2004).
44. Adachi, O. et al. Targeted disruption of the MyD88 gene resulted in impaired IL-1- and IL-18-mediated function. Immunity 9, 143-150 (1998).
45. Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115-122 (1999). Provides the first evidence for the existence of the MyD88-independent pathway.
46. Kawai, T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167, 5887-5894 (2001).
47. Hoshino, K., Kaisho, T., Iwabe, T., Takeuchi, O. & Akira, S. Differential involvement of IFN-β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14, 1225-1231 (2002).
48. Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nature Immunol. 3, 392-398 (2002).
49. Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166, 5688-5694 (2001).
50. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301, 640-643 (2003).
51. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743-748 (2003). References 50 and 51 demonstrate that TRIF is an essential adaptor in the TLR3- and TLR4-mediated MyD88-independent pathway.
52. Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732-738 (2001).
53. Homg, T., Barton, G. M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nature Immunol. 2, 835-841 (2001).
54. Fitzgerald, K. A. et al. Mal (MyD88-adaptor-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78-83 (2001).
55. Yamamoto, M. et al. Essential role of TIRAP/Mal for activation of the signaling cascade shared by TLR2 and TLR4. Nature 420, 324-329 (2002).
56. Horng, T., Barton, G. M., Flavell, R. A. & Medzhitov, R. The adaptor molecule TIRAP provides signaling specificity for Toll-like receptors. Nature 420, 329-333 (2002). References 55 and 56 show that TIRAP is essential for the TLR2- and TLR4-mediated MyD88-dependent pathway.
57. Yamamoto, M. et al. A novel TIR domain-containing adaptor that preferentially activates the interferon-β promoter. J. Immunol. 169, 6668-6672 (2002).
58. Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nature Immunol. 4, 161-167 (2003).
59. Bin, L. H., Xu, L. G. & Shu, H. B. TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling. J. Biol. Chem. 278, 24526-24532 (2003).
60. Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunol. 4, 1144-1150 (2003).
61. Fitzgerald, K. A. et al. LPS-TLR4 signaling to IRF-3/7 and NF-κB involves the Toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043-1055 (2003).
62. Oshiumi, H. et al. TIR-containing adapter molecule (TICAM-2: a bridging adapter recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-β. J. Biol. Chem. 278, 49751-49762 (2003). References 60 to 62 show the involvement of the TIR-domain-containing adaptor TRAM in the TLR4-mediated, MyD88-independent/TRIF-dependent pathway.
63. O'Neill, L. A., Fitzgerald, K. A. & Bowie, A. G. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol. 24, 286-290 (2003).
64. Couillault, C. et al. TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nature Immunol. 5, 488-494 (2004).
65. Yoneyama, M. et al. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J. 17, 1087-1095 (1998).
66. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623-655 (2001).
67. Barnes, B., Lubyova, B. & Pitha, P. M. On the role of IRF in host defense. J. Interferon Cytokine Res. 22, 59-71 (2002).
68. Taniguchi, T. & Takaoka, A. The interferon-α/β system in artiviral responses: a multimodal machinery of gene regulation by the IRF family of transcription factors. Curr. Opin. Immunol. 14, 111-116 (2002).
69. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539-548 (2000).
70. Servant, M. J. et al. Identification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA. J. Biol. Chem. 278, 9441-9447 (2003).
71. Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148-1151 (2003).
72. Fitzgerald, K. A. et al. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nature Immunol. 4, 491-496 (2003). References 71 and 72 describe the identification of non-canonical IKKs as kinases that activate IRF3.
73. McWhirter, S.M. et al. IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl Acad. Sci. USA 101, 233-238 (2004).
74. Sato, S. et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-κB and IFN-regulatory factor-3, in the Toll-like receptor signaling. J. Immunol. 171, 4304-4310 (2003).
75. Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nature Immunol. 5, 503-507 (2004).
76. Bums, K. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biol. 2, 346-351 (2000).
77. Zhang, G. & Ghosh, S. Negative regulation of Toll-like receptor-mediated signaling by Tollip. J. Biol. Chem. 277, 7059-7065 (2002).
78. Grosshans, J., Schnorrer, F. & Nusslein-Volhard, C. Oligomerisation of Tube and Pelle leads to nuclear localisation of Dorsal. Mech. Dev. 81, 127-138 (1999).
79. Yu, K. et al. Cutting edge: Mouse pellino-2 modulates IL-1 and lipopolysaccharide signaling. J. Immunol. 169, 4075-4078 (2002).
80. Jiang, Z. et al. Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex. J. Biol. Chem. 278, 10952-10956 (2003).
81. Jensen, L. E. & Whitehead, A. S. Pellino, a novel member of the pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein. J. Immunol. 171, 1500-1506 (2003).
82. Koyasu, S. The role of PI3K in immune cells. Nature Immunol. 4, 313-319 (2003).
83. Arbibe, L. et al. Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nature Immunol. 1, 533-540 (2000).
84. Ojaniemi, M. et al. Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur. J. Immunol. 33, 597-605 (2003).
85. Li, X. et al. Phosphoinositide 3 kinase mediates Toll-like receptor 4-induced activation of NF-κB in endothelial cells. Infect. Immun. 71, 4414-4420 (2003).
86. Fukao, T. et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nature Immunol. 3, 875-881 (2002).
87. Kopp, E. et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 13, 2059-2071 (1999).
88. Xiao, C. et al. Ecsit is required for BMP signaling and mesoderm formation during mouse embryogenesis. Genes Dev. 17, 2933-2949 (2003).
89. Jefferies, C. A. et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor κB activation by Toll-like receptor 4. J. Biol. Chem. 278, 26258-26264 (2003).
90. Meng, F. & Lowell, C. A. Lipopolysaccharide (LPS)-induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn. J. Exp. Med. 185, 1661-1670 (1997).
91. Huang, Q. et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nature Immunol. 5, 98-103 (2003).
92. Dumitru, C. D. et al. TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103, 1071-1083 (2000).
93. Kobayashi, K. et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191-202 (2002).
94. Yasukawa, H., Sasaki, A. & Yoshimura, A. Negative regulation of cytokine signaling pathways. Annu. Rev. Immunol. 18,143-164 (2000).
95. Stoiber, D. et al. Lipopolysaccharide induces in macrophages the synthesis of the suppressor of cytokine signaling 3 and suppresses signal transduction in response to the activating factor IFN-γ. J. Immunol. 163, 2640-2647 (1999).
96. Dalpke, A. H., Opper, S., Zimmermann, S. & Heeg, K. Suppressors of cytokine signaling (SOCS)-1 and SOCS-3 are induced by CpG-DNA and modulate cytokine responses in APCs. J. Immunol. 166, 7082-7089 (2001).
97. Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583-591 (2002).
98. Nakagawa, R. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677-687 (2002).
99. Bums, K. et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J. Exp. Med. 197, 263-268 (2003).
100. Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature Immunol. 4, 920-927 (2003).
101. Brint, E. K. et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature Immunol. 5, 373-379 (2004).
102. Takeuchi, O., Hoshino, K. & Akira, S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immunol. 165, 5392-5396 (2000).
103. Sugawara, I., Yamada, H., Mizuno, S., Takeda, K. & Akira, S. Mycobacterial infection in MyD88-deficient mice. Microbiol. Immunol. 47, 841-847 (2003).
104. Seki, E. et al. Critical roles of myeloid differentiation factor 88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes in mice. J. Immunol. 169, 3863-3868 (2002).
105. Way, S. S., Kollmann, T. R., Hajjar, A. M. & Wilson, C. B. Cutting edge: Protective cell-mediated immunity to Listeria monocytogenes in the absence of myeloid differentiation factor 88. J. Immunol. 171, 533-537 (2003).
106. Serbina, N. Y. et al. Sequential MyD88-independent and -dependent activation of innate immune responses to intracellular bacterial infection. Immunity 19, 891-901 (2003).
107. Inohara, N. & Nunez, G. NODs: intracellular proteins involved in inflammation and apoptosis. Nature Rev. Immunol. 3, 371-382 (2003).
108. Hoebe, K. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nature Immunol. 4, 1223-1229 (2003).
109. Diebold, S. S. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324-328 (2003).
110. Abraham, N. et al. Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR. J. Biol. Chem. 274, 5953-5962 (1999).
111. Honda, K. et al. Selective contribution of IFN-α/β signaling to the maturation of dendritic cells induced by double-stranded RNA or viral infection. Proc. Natl Acad. Sci. USA 100, 10872-10877 (2003).
112. Takeuchi, O. et al. Cutting edge: Role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J. Immunol, 169, 10-14 (2002).
113. Wyllie, D. H. et al. Evidence for an accessory protein function for Toll-like receptor 1 in anti-bacterial responses. J. Immunol. 165, 7125-7132 (2002).
114. Aliprantis, A. O. et al. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor 2. Science 285, 736-739 (1999).
115. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in racognition of Gram-negative and Gram-positive cell wall components. Immunity 11, 443-451 (1999).
116. Schwadner, R. et al. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J. Biol. Chem. 274, 17406-17409 (1999).
117. Means, T. K. et al. Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163, 3920-3977 (1999).
118. Hajjar, A. M. et al. 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 (2001).
119. Coelho, P. S. et al. Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes induce in vivo leukocyte recruitment dependent on MCP-1 production by IFN-γ-primed- macrophages. J. Leukoc. Biol. 71, 837-844 (2002).
120. Opitz, B. et al. Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-κB translocation. J. Biol. Chem. 276, 22041-22047 (2001).
121. Massari, P. et al. Cutting edge: Immune stimulation by Neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168, 1533-1537 (2002).
122. Werts, C. et al. Leptospiral liopolysaccharide activates cells through a TLR2-dependent mechanism. Nature Immunol. 2, 346-352 (2001).
123. Hirschfeld, M. et al. Signaling by Toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect. Immun. 69, 1477-1482 (2001).
124. Underhill D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811-815 (1999).
125. Asea, A. et al. Novel signal transduction pathway utilized by extracellular HSP70: role of Toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277, 15028-15034 (2002).
126. Kawasaki, K. et al. Mouse Toll-like receptor 4-MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by taxol. J. Biol Chem. 275, 2251-2254 (2000).
127. Kurt-Jones, E. A. et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nature Immunol. 1, 398-401 (2000).
128. Rassa, J. C. et al. Murine retroviruses activate B cells via interaction with Toll-like receptor 4. Proc. Natl Acad. Sci. USA 99, 2281-2286 (2002).
129. Bulut, Y. et al. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J. Immunol. 168, 1435-1440 (2002).
130. Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Cutting edge: Heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. J. Immunol. 164, 558-561 (2000).
131. Vabulas, R. M. et al. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107-15112 (2002).
132. Okamura, Y. et al. The extra domain A of fibronectin activates Toll-like receptor 4. J. Biol. Chem. 276, 10229-10233 (2001).
133. Termeer, C. et al. Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J. Exp. Med. 195, 99-111 (2002).
134. Johnson, G. B., Brunn, G. J., Kodaira, Y. & Platt, J. L. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J. Immunol. 168, 5233-5239 (2002).
135. Smiley, S. T., King, J. A. & Hancock, W. W. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J. Immunol. 167, 2887-2894 (2001).
136. Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor-5. Nature 410, 1099-1103 (2001).
137. Takeuchi, O. et al. Discrimination of bacterial lipopeptides by Toll-like receptor 6. Int. Immunol. 13, 933-940 (2001).
138. Ozinsky, A. et al. 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 (2000).
139. Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nature Immunol. 3, 196-200 (2002).
140. Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526-1529 (2004).
141. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529-1531 (2004).
142. Jurk, M. et al. Human TLR or TLR8 independently confer responsiveness to the antiviral compound R-848. Nature Immunol. 3, 499 (2002).
143. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740-745 (2000).
144. Zhang, D. et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522-1526 (2004).