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Chapter 13 : Toll-Like Receptors: Ligands and Signaling

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Abstract:

This chapter focuses on recent advances in one's understanding of the function of toll-like receptors (TLRs), particularly with regard to their ligands and signaling. Fibrinogen has been shown to induce the production of chemokines from macrophages through recognition by TLR4. Thus, TLR4 is presumably involved in several inflammatory responses by recognizing endogenous ligands even in the absence of infection. Therefore, more careful experiments are required before one can conclude that TLR4 recognizes these endogenous ligands. The signaling pathways via TLRs originate from the Toll/interleukin-1 receptor (TIR) domain. MyD88 harboring the TIR domain in the carboxy-terminal portion associates with the TIR domain of TLRs. MyD88-deficient mice showed impaired responses to the IL-1 family of cytokines, whose receptors have the cytoplasmic TIR domain. IFN-α has been shown to be induced in response to the activation of TLR7 as well as TLR4. In attempts to characterize the MyD88-independent signaling pathway, a second adaptor molecule containing the TIR domain was identified and designated TIR adaptor protein (TIRAP) or MyD88- adaptor-like. Initial in vitro studies suggested that TIRAP specifically associates with TLR4 and acts as an adaptor in the MyD88-independent signaling pathway. These studies further indicate that the TIR domain-containing molecules provide the specificity for individual TLR-mediated signaling pathways. Elucidation of the signaling pathway that is specific to each TLR will provide one with an important clue to understanding the molecular mechanisms by which innate immunity is activated and finally lead to the development of antigen-specific adaptive immunity.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13

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Figures

Image of FIGURE 1
FIGURE 1

TLRs and their ligands. TLR2 is essential in the recognition of microbial lipopeptides.TLR1 and TLR6 cooperate with TLR2 to discriminate subtle differences between triacyl and diacyl lipopeptides, respectively. TLR4 is the receptor for LPS. TLR9 is essential in CpG DNA recognition, whereas TLR3 is implicated in the recognition of viral dsRNA. TLR5 recognizes flagellin. Thus, the TLR family members recognize specific patterns of bacterial components.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 2
FIGURE 2

The LPS receptor complex. The LPS receptor comprises several components. TLR4 is an essential receptor component for the signal transduction via the LPS receptor complex. MD-2 associates with the extracellular portion of TLR4 and is involved in the LPS recognition. LBP is a soluble molecule that binds to the lipid A portion of LPS. The LPS–LBP complex binds to CD14 and then this complex associates with TLR4. In B cells, additional components, RP105 and MD-1, are involved in the LPS recognition.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 3
FIGURE 3

MyD88-dependent signaling pathway. A TIR domain-containing adaptor molecule, MyD88, associates with the cytoplasmic TIR domain of TLRs and recruits IRAKs to the receptor upon receptor activation. IRAKs then activate TRAF6, leading to the activation of MAP kinases and NF-κB. TIRAP, a second TIR domain-containing adaptor, is involved in the MyD88-dependent signaling pathway via TLR2 and TLR4.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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Image of FIGURE 4
FIGURE 4

MyD88-independent signaling pathway. In the TLR3- and TLR4-mediated signaling pathways, LPS-induced activation of IRF-3 is observed in MyD88-deficient mice, indicating the presence of a MyD88-independent pathway. It remains unclear how IRF-3 is activated. Recently, a TIR domain-containing adaptor, TRIF, was found to associate with IRF-3 and TLR3, indicating a possible role for TRIF in the MyD88-independent pathway.

Citation: Takeda K, Akira S. 2004. Toll-Like Receptors: Ligands and Signaling, p 257-270. In Kaufmann S, Medzhitov R, Gordon S (ed), The Innate Immune Response to Infection. ASM Press, Washington, DC. doi: 10.1128/9781555817671.ch13
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References

/content/book/10.1128/9781555817671.chap13
1. Adachi, O.,, T. Kawai,, K. Takeda,, M. Matsumoto,, H. Tsutsui,, M. Sakagami,, K. Nakanishi,, and S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9: 143 150.
2. Akashi, S.,, R. Shimazu,, H. Ogata,, Y. Nagai,, K. Takeda,, M. Kimoto,, and K. Miyake. 2000. Cutting edge: cell surface expression and lipopolysaccharide signaling via the Toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages. J. Immunol. 164: 3471 3475.
3. Akashi, S.,, Y. Nagai,, H. Ogata,, M. Oikawa,, K. Fukase,, S. Kusumoto,, K. Kawasaki,, M. Nishijima,, S. Hayashi,, M. Kimoto,, and K. Miyake. 2001. Human MD-2 confers on mouse Toll-like receptor 4 species-specific lipopolysaccharide recognition. Int. Immunol. 13: 1595 1599.
4. Alexopoulou, L.,, A. C. Holt,, R. Medzhitov,, and R. A. Flavell. 2001. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413: 732 738.
5. Alexopoulou, L.,, V. Thomas,, M. Schnare,, Y. Lobet,, J. Anguita,, R.T. Schoen,, R. Medzhitov,, E. Fikrig,, and R. A. Flavell. 2002. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat. Med. 8: 878 884.
6. Asea, A.,, M. Rehli,, E. Kabingu,, J. A. Boch,, O. Bare,, P. E. Auron,, M. A. Stevenson,, and S. K. Calderwood. 2002. Novel signal transduction pathway utilized by extracellular HSP70: role of TLR2 and TLR4. J. Biol. Chem. 277: 15028 15034.
7. Bulut, Y.,, E. Faure,, L. Thomas,, O. Equils,, and M. Arditi. 2002. Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling. J. Immunol. 167: 987 994.
8. Burns, K.,, J. Clatworthy,, L. Martin,, F. Martinon,, C. Plumpton,, B. Maschera,, A. Lewis,, K. Ray,, J. Tschopp,, and F. Volpe. 2000. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat. Cell Biol. 2: 346 351.
9. Campos, M. A.,, I. C. Almeida,, O. Takeuchi,, S. Akira,, E. P. Valente,, D. O. Procopio,, L. R. Travassos,, J. A. Smith,, D. T. Golenbock,, and R. T. Gazzinelli. 2001. Activation of Toll-like receptor- 2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 167: 416 423.
10. Chin, A. I.,, P.W. Dempsey,, K. Bruhn,, J. F. Miller,, Y. Xu,, and G. Cheng. 2002. Involvement of receptor- interacting protein 2 in innate and adaptive immune responses. Nature 416: 190 194.
11. Da Shilva Correia, J.,, K. Soldau,, U. Christen,, P. S. Tobias,, and R. J. Ulevitch. 2001. Lipopoly- saccharide is in close proximity to each of the protein in its membrane receptor complex. J. Biol. Chem. 276: 21129 21135.
12. Doyle, S. E.,, S. A. Vaidya,, R. O'Connell,, H. Dadgostar,, P.W. Dempsey,, T.-T. Wu,, G. Rao,, R. Sun,, M. E. Haberland,, R. L. Modlin,, and G. Cheng. 2002. IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity 17: 251 263.
13. Dybdahl, B.,, A. Wahba,, E. Lien,, T. H. Flo,, A. Waage,, N. Qureshi,, O. F. Sellevold,, T. Espevik,, and A. Sundan. 2002. Inflammatory response after open heart surgery: release of heat-shock protein 70 and signaling through toll-like receptor-4. Circulation 105: 685 690.
14. Fitzgerald, K. A.,, E. M. Palsson-McDermott,, A. G. Bowie,, C. Jefferies,, A. S. Mansell,, G. Brady,, E. Brint,, A. Dunne,, P. Gray,, M. T. Harte,, D. McMurray,, D. E. Smith,, J. E. Sims,, T. A. Bird,, and L. A. J. O'Neill. 2001. Mal (MyD88-adaptorlike) is required for Toll-like receptor-4 signal transduction. Nature 413: 78 83.
15. Gao, B.,, and M. F. Tsan. 2003. Endotoxin contamination in recombinant human Hsp70 preparation is responsible for the induction of tumor necrosis factor α release by murine macrophages. J. Biol. Chem. 278: 174 179.
16. Hacker, H.,, R. M. Vabulas,, O. Takeuchi,, K. Hoshino,, S. Akira,, and H. Wagner. 2000. Immune cell activation by bacterial CpG-DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor-associated factor (TRAF)6. J. Exp. Med. 192: 595 600.
17. Hajjar, A. M.,, D. S. O'Mahony,, A. Ozinsky,, D.M. Underhill,, A. Aderem,, S. J. Klebanoff,, and C. B. Wilson. 2001. 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.
18. Hayashi, F.,, K.D. Smith,, A. Ozinsky,, T. R. Hawn,, E. C. Yi,, D. R. Goodlett,, J. K. Eng,, S. Akira,, D. M. Underhill,, and A. Aderem. 2001. The innate immune response to bacterial flagellin is mediated by Toll-like receptor-5. Nature 410: 1099 1103.
19. Haynes, L. M.,, D. D. Moore,, E. A. Kurt-Jones,, R. W. Finberg,, L. J. Anderson,, and R. A. Tripp. 2001. Involvement of Toll-like receptor 4 in innate immunity to respiratory syncytial virus. J. Virol. 75: 10730 10737.
20. Haziot, A.,, E. Ferrero,, F. Kontgen,, N. Hijiya,, S. Yamamoto,, J. Silver,, C. L. Stewart,, and S. M. Goyert. 1996. Resistance to endotoxin shock and reduced dissemination of gram negative bacteria in CD14-deficient mice. Immunity 4: 407 414.
21. Hemmi, H.,, O. Takeuchi,, T. Kawai,, T. Kaisho,, S. Sato,, H. Sanjo,, M. Matsumoto,, K. Hoshino,, H. Wagner,, K. Takeda,, and S. Akira. 2000. A Toll-like receptor recognizes bacterial DNA. Nature 408: 740 745.
22. Hemmi, H.,, T. Kaisho,, O. Takeuchi,, S. Sato,, H. Sanjo,, K. Hoshino,, T. Horiuchi,, H. Tomizawa,, K. Takeda,, and S. Akira. 2002. Small antiviral compounds activate immune cells via TLR7 MyD88- dependent signalling pathway. Nat. Immunol. 3: 196 200.
23. Horng, T.,, G. M. Barton,, and R. Medzhitov. 2001. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2: 835 841.
24. Horng, T.,, G. M. Barton,, R. A. Flavell,, and R. Medzhitov. 2002. The adaptor molecule TIRAP provides signaling specificity for Toll-like receptors. Nature 420: 329 333.
25. Hoshino, K.,, O. Takeuchi,, T. Kawai,, H. Sanjo,, T. Ogawa,, Y. Takeda,, K. Takeda,, and S. Akira. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162: 3749 3752.
26. Hoshino, K.,, T. Kaisho,, T. Iwabe,, O. Takeuchi,, and S. Akira. 2002. Differential involvement of IFN- β in Toll-like receptor-stimulated dendritic cell activation. Int. Immunol. 14: 1225 1231.
27. Inohara, N.,, L. del Peso,, T. Koseki,, S. Chen,, and G. Nunez. 1998. RICK, a novel protein kinase containing a caspase recruitment domain, interacts with CLARP and regulates CD95-mediated apoptosis. J. Biol. Chem. 273: 12296 12300.
28. Ito, T.,, R. Amakawa,, T. Kaisho,, H. Hemmi,, K. Tajima,, K. Uehira,, Y. Ozaki,, H. Tomizawa,, S. Akira,, and S. Fukuhara. 2002. Interferon-α and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. J. Exp. Med. 195: 1507 1512.
29. Jack, R. S.,, X. Fan,, M. Bernheiden,, G. Rune,, M. Ehlers,, A. Weber,, G. Kirsch,, R. Mentel,, B. Furll,, M. Freudenberg,, G. Schmitz,, F. Stelter,, and C. Schutt. 1997. Lipopolysaccharide-binding protein is required to combat a murine gram-negative bacterial infection. Nature 389: 742 745.
30. Jiang, Q.,, S. Akashi,, K. Miyake,, and H. R. Petty. 2000. Cutting edge: lipopolysaccharide induces physical proximity between CD14 and Toll-like receptor 4 (TLR4) prior to nuclear translocation of NF-κB. J. Immunol. 165: 3541 3544.
31. Johnson, G. B.,, G. J. Brunn,, Y. Kodaira,, and J. L. Platt. 2002. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J. Immunol. 168: 5233 5239.
32. Kaisho, T.,, O. Takeuchi,, T. Kawai,, K. Hoshino,, and S. Akira. 2001. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166: 5688 5694.
33. Kanakaraj, P.,, K. Ngo,, Y. Wu,, A. Angulo,, P. Ghazal,, C. A. Harris,, J. J. Siekierka,, P. A. Peterson,, and W. P. Fung-Leung. 1998. 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.
34. Kataoka, K.,, T. Muta,, S. Yamazaki,, and K. Takeshige. 2002. Activation of macrophages by linear (1-3)-β-D-glucans. Implications for the recognition of fungi by innate immunity. J. Biol. Chem. 277: 36825 36831.
35. Kawai, T.,, O. Adachi,, T. Ogawa,, K. Takeda,, and S. Akira. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11: 115 122.
36. Kawai, T.,, O. Takeuchi,, T. Fujita,, J. Inoue,, P. F. Muhlradt,, S. Sato,, K. Hoshino,, and S. Akira. 2001. Lipopolysaccharide stimulates the MyD88- independent pathway and results in activation of IRF- 3 and the expression of a subset of LPS-inducible genes. J. Immunol. 167: 5887 5894.
37. Kobayashi, K.,, N. Inohara,, L.D. Hernandez,, J. E. Galan,, G. Nunez,, C. A. Janeway,, R. Medzhitov,, and R. A. Flavell. 2002. RICK/Rip2/CARDIAK mediates signaling for receptors of the innate and adaptive immune systems. Nature 416: 194 199.
38. Krug, A., S, Rothenfusser, V. Hornung, B. Jahrsdorfer, S. Blackwell, Z. K. Ballas, S. Endres, A. M. Krieg, and G. Hartmann. 2001. Identification of CpG oligonucleotide sequences with high induction of IFN-α/β in plasmacytoid dendritic cells. Eur. J. Immunol. 31: 2154 2163.
39. Kurt-Jones, E. A.,, L. Popova,, L. Kwinn,, L. M. Haynes,, L. P. Jones,, R. A. Tripp,, E. E. Walsh,, M.W. Freeman,, D.T. Golenbock,, L. J. Anderson,, and R.W. Finberg. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat. Immunol. 1: 398 401.
40. Lehner, M. D.,, S. Morath,, K. S. Michelsen,, R. R. Schumann,, and T. Hartung. 2001. Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different toll-like receptors independent of paracrine mediators. J. Immunol. 166: 5161 5167.
41. Lemaitre, B.,, E. Nicolas,, L. Michaut,, J.-M. Reichhart,, and J. A. Hoffmann. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86: 973 983.
42. Li, S.,, A. Strelow,, E. J. Fontana,, and H. Wesche. 2002. IRAK-4—a novel member of the IRAK family with the properties of an IRAK-kinase. Proc. Natl. Acad. Sci. USA 99: 5567 5572.
43. Lomaga, M. A.,, W. C. Yeh,, I. Sarosi,, G. S. Duncan,, C. Furlonger,, A. Ho,, S. Morony,, C. Capparelli,, G. Van,, S. Kaufman,, A. van der Heiden,, A. Itie,, A. Wakeham,, W. Khoo,, T. Sasaki,, Z. Cao,, J. M. Penninger,, C. J. Paige,, D. L. Lacey,, C. R. Dunstan,, W. J. Boyle,, D.V. Goeddel,, and T. W. Mak. 1999. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13: 1015 1024.
44. Massari, P.,, P. Henneke,, Y. Ho,, E. Latz,, D. T. Golenbock,, and L. M. Wetzler. 2002. Cutting edge: immune stimulation by neisserial porins is Toll-like receptor 2 and MyD88 dependent. J. Immunol. 168: 1533 1537.
45. Matsumoto, M.,, S. Kikkawa,, M. Kohase,, K. Miyake,, and T. Seya. 2002. Establishment of a monoclonal antibody against human Toll-like receptor 3 that blocks double-stranded RNA-mediated signaling. Biochem. Biophys. Res. Commun. 293: 1364 1369.
46. McCarthy, J.V.,, J. Ni,, and V. M. Dixit. 1998. RIP2 is a novel NF-κB-activating and cell death-inducing kinase. J. Biol. Chem. 273: 16968 16975.
47. Means, T. K.,, S. Wang,, E. Lien,, A. Yoshimura,, D. T. Golenbock,, and M. J. Fenton. 1999a. Human Toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163: 3920 3927.
48. Means, T. K.,, E. Lien,, A. Yoshimura,, S. Wang,, D. T. Golenbock,, and M. J. Fenton. 1999b. The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. J. Immunol. 163: 6748 6755.
49. Medzhitov, R.,, P. Preston-Hurlburt,, and C. A. Janeway, Jr. 1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388: 394 397.
50. Miyake, K.,, Y. Yamashita,, M. Ogata,, T. Sudo,, and M. Kimoto. 1995. RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucin-rich repeat protein family. J. Exp. Med. 154: 3333 3340.
51. Miyake, K.,, R. Shimazu,, J. Kondo,, T. Niki,, S. Akashi,, H. Ogata,, Y. Yamashita,, Y. Miura,, and M. Kimoto. 1998. MD-1, a molecule that is physically associated with RP105 and positively regulates its expression. J. Immunol. 161: 1348 1353.
52. Moore, K. J.,, L. P. Anderson,, R. R. Ingalls,, B. G. Monks,, R. Li,, M. A. Arnaout,, D. T. Golenbock,, and M. W. Freeman. 2000. Divergent response to LPS and bacteria in CD14-deficient murine macrophages. J. Immunol. 165: 4272 4280.
53. Nagai, Y.,, S. Akashi,, M. Nagafuku,, M. Ogata,, Y. Iwakura,, S. Akira,, T. Kitamura,, A. Kosugi,, M. Kimoto,, and K. Miyake. 2002. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat. Immunol. 3: 667 672.
54. Naito, A.,, S. Azuma,, S. Tanaka,, T. Miyazaki,, S. Takaki,, K. Takatsu,, K. Nakao,, K. Nakamura,, M. Katsuki,, T. Yamamoto,, and J. Inoue. 1999. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4: 353 362.
55. Navarro, L.,, and M. David. 1999. p38-dependent activation of interferon regulatory factor 3 by lipopolysaccharide. J. Biol. Chem. 274: 35535 35538.
56. Nomura, F.,, S. Akashi,, Y. Sakao,, S. Sato,, T. Kawai,, M. Matsumoto,, K. Nakanishi,, M. Kimoto,, K. Miyake,, K. Takeda,, and S. Akira. 2000. Endotoxin tolerance in mouse peritoneal macrophages correlates with downregulation of surface Toll-like receptor 4 expression. J. Immunol. 164: 3476 3479.
57. Ogata, H.,, I. Su,, K. Miyake,, Y. Nagai,, S. Akashi,, I. Mecklenbrauker,, K. Rajewski,, M. Kimoto,, and A. Tarakhovsky. 2000. The Toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J. Exp. Med. 192: 23 29.
58. Ohashi, K.,, V. Burkart,, S. Flohe,, and H. Kolb. 2000. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164: 558 561.
59. Okamura, Y.,, M. Watari,, E. S. Jerud,, D.W. Young,, S.T. Ishizaka,, J. Rose,, J. C. Chow,, and J. F. Strauss III. 2001. The extra domain A of fibronectin activates Toll-like receptor 4. J. Biol. Chem. 276: 10229 10233.
60. Opitz, B.,, N. W. Schroder,, I. Spreitzer,, K. S. Michelsen,, C. J. Kirschning,, W. Hallatschek,, U. Zahringer,, T. Hartung,, U. B. Gobel,, and R. R. Schumann. 2001. Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-κB translocation. J. Biol. Chem. 276: 22041 22047.
61. Ozinsky, A.,, D. M. Underhill,, J. D. Fontenot,, A. M. Hajjar,, K. D. Smith,, C. B. Wilson,, L. Schroeder,, and A. Aderem. 2000. 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.
62. Poltorak, A.,, X. He,, I. Smirnova,, M.Y. Liu,, C.V. Huffel,, X. Du,, D. Birdwell,, E. Alejos,, M. Silva,, C. Galanos,, M. Freudenberg,, P. Ricciardi- Castagnoli,, B. Layton,, and B. Beutler. 1998. Defective LPS signaling in C3H/HeJ and C57BL/ 10ScCr mice: mutation in Tlr4 gene. Science 282: 2085 2088.
63. Qureshi, S. T.,, L. Lariviere,, G. Leveque,, S. Clermont,, K. J. Moore,, P. Gros,, and D. Malo. 1999. Endotoxin-tolerant mice have mutations in Tolllike receptor 4 ( Tlr4 ). J. Exp. Med. 189: 615 625.
64. Rassa, J. C.,, J. L. Meyers,, Y. Zhang,, R. Kudaravalli,, and S. R. Ross. 2002. Murine retroviruses activate B cells via interaction with Toll-like receptor 4. Proc. Natl. Acad. Sci. USA 99: 2281 2286.
65. Ropert, C.,, L. R. Ferreira,, M. A. Campos,, D. O. Procopio,, L. R. Travassos,, M. A. Ferguson,, L. F. Reis,, M. M. Teixeira,, I. C. Almeida,, and R. T. Gazzinelli. 2002. Macrophage signaling by glycosylphosphatidylinositol- anchored mucin-like glycoproteins derived from Trypanosoma cruzi trypomastigotes. Microbes Infect. 4: 1015 1025.
66. Sato, M.,, H. Suemori,, N. Hata,, M. Asagiri,, K. Ogasawara,, K. Nakao,, T. Nakaya,, M. Katsuki,, S. Noguchi,, N. Tanaka,, and T. Taniguchi. 2000. 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.
67. Schnare, M.,, A. C. Holt,, K. Takeda,, S. Akira,, and R. Medzhitov. 2000. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr. Biol. 10: 1139 1142.
68. Schromm, A. B.,, E. Lien,, P. Henneke,, J. C. Chow,, A. Yoshimura,, H. Heine,, E. Latz,, B. G. Monks,, D. A. Schwartz,, K. Miyake,, and D.T. Golenbock. 2001. Molecular genetic analysis of an endotoxin nonresponder mutant cell line: a point mutation in a conserved region of MD-2 abolishes endotoxin-induced signaling. J. Exp. Med. 194: 79 88.
69. Schumann, R. R.,, S. R. Leong,, G.W. Flaggs,, P. W. Gray,, S. D. Wright,, J. C. Mathison,, P. S. Tobias,, and R. Ulevitch. 1990. Structure and function of lipopolysaccharide binding protein. Science 249: 1429 1431.
70. Schwandner, R.,, R. Dziarski,, H. Wesche,, M. Rothe,, and C. J. Kirschning. 1999. Peptidoglycanand lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J. Biol. Chem. 274: 17406 17409.
71. Seki, E.,, H. Tsutsui,, H. Nakano,, N. Tsuji,, K. Hoshino,, O. Adachi,, K. Adachi,, S. Futatsugi,, K. Kuida,, O. Takeuchi,, H. Okamura,, J. Fujimoto,, S. Akira,, and K. Nakanishi. 2001. Lipopolysaccharide- induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1β. J. Immunol. 166: 2651 2657.
72. Shimazu, R.,, S. Akashi,, H. Ogata,, Y. Nagai,, K. Fukudome,, K. Miyake,, and M. Kimoto. 1999. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189: 1777 1782.
73. Smiley, S.T.,, J.A. King,, and W.W. Hancock. 2001. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J. Immunol. 167: 2887 2894.
74. Suzuki, N.,, S. Suzuki,, G. S. Duncan,, D.G. Millar,, T. Wada,, C. Mirtsos,, H. Takada,, A. Wakeham,, A. Itie,, S. Li,, J. M. Penninger,, H. Wesche,, P. S. Ohashi,, T. W. Mak,, and W. C. Yeh. 2002. Severe impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4. Nature. 416: 750 756.
75. Swantek, J. L.,, M. F. Tsen,, M. H. Cobb,, and J. A. Thomas. 2000. IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. J. Immunol. 164: 4301 4306.
76. Takeuchi, O.,, K. Hoshino,, T. Kawai,, H. Sanjo,, H. Takada,, T. Ogawa,, K. Takeda,, and S. Akira. 1999. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive cell wall components. Immunity 11: 443 451.
77. Takeuchi, O.,, K. Hoshino,, and S. Akira. 2000a. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J. Immunol. 165: 5392 5396.
78. Takeuchi, O.,, A. Kaufmann,, K. Grote,, T. Kawai,, K. Hoshino,, M. Morr,, P. F. Muhlradt,, and S. Akira. 2000b. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophageactivating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164: 554 557.
79. Takeuchi, O.,, K. Takeda,, K. Hoshino,, O. Adachi,, T. Ogawa,, and S. Akira. 2000c. Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int. Immunol. 12: 113 117.
80. Takeuchi, O.,, T. Kawai,, P. F. Muhlradt,, J. D. Radolf,, A. Zychlinsky,, K. Takeda,, and S. Akira. 2001. Discrimination of bacterial lipopeptides by Tolllike receptor 6. Int. Immunol. 13: 933 940.
81. Takeuchi, O.,, T. Horiuchi,, K. Hoshino,, K. Takeda,, Z. Dong,, R. L. Modlin,, and S. Akira. 2002. Role of TLR1 in mediating immune response to microbial lipoproteins. J. Immunol. 169: 10 14.
82. Termeer, C.,, F. Benedix,, J. Sleeman,, C. Fieber,, U. Voith,, T. Ahrens,, K. Miyake,, M. Freudenberg,, C. Galanos,, and J. C. Simon. 2002. Oligosaccharides of hyaluronan activate dendritic cells via Tolllike receptor 4. J. Exp. Med. 195: 99 111.
83. Thomas, J. A.,, J. L. Allen,, M. Tsen,, T. Dubnicoff,, J. Danao,, X. C. Liao,, Z. Cao,, and S. A. Wasserman. 1999. Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J. Immunol. 163: 978 984.
84. Tobias, P.,, K. Soldau,, and R. Ulevitch. 1986. Isolation of a lipopolysaccharide-binding acute phase reactant from rabbit serum. J. Exp. Med. 164: 777 793.
85. Toshchakov, V.,, B. W. Jones,, P. Y. Perera,, K. Thomas,, M. J. Cody,, S. Zhang,, B. R. Williams,, J. Major,, T. A. Hamilton,, M. J. Fenton,, and S. N. Vogel. 2002. TLR4, but not TLR2, mediates IFN-β- induced STAT1α/β-dependent gene expression in macrophages. Nat. Immunol. 3: 392 398.
86. Underhill, D. M.,, A. Ozinsky,, K. D. Smith,, and A. Aderem. 1999a. Toll-like receptor 2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc. Natl. Acad. Sci. USA 96: 14459 14463.
87. Underhill, D. M.,, A. Ozinsky,, A. M. Hajjar,, A. Stevens,, C. B. Wilson,, M. Bassetti,, and A. Aderem. 1999b. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401: 811 815.
88. Vabulas, R. M.,, P. Ahmad-Nejad,, C. da Costa,, T. Miethke,, C. J. Kirschning,, H. Hacker,, and H. Wagner. 2001. Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J. Biol. Chem. 276: 31332 31339.
89. Vabulas, R. M.,, P. Ahmad-Nejad,, S. Ghose,, C. J. Kirschning,, R. D. Issels,, and H. Wagner. 2002. HSP70 as endogenous stimulus of toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277: 15107 15112.
90. Weaver, B. K.,, K. P. Kumar,, and N. C. Reich. 1998. Interferon regulatory factor 3 and CREB-binding protein/p300 are subunits of double-stranded RNA-activated transcription factor DRAF1. Mol. Cell. Biol. 18: 1359 1368.
91. Wurfel, M. M.,, B. G. Monks,, R. R. Ingalls,, R. L. Dedrick,, R. Delude,, D. Zhou,, N. Lamping,, R. R. Schumann,, R. Thieringer,, M. J. Fenton,, S. D. Wright,, and D. Golenbock. 1997. Targeted deletion of the lipopolysaccharide (LPS)-binding protein gene leads to profound suppression of LPS responses ex vivo, whereas in vivo responses remain intact. J. Exp. Med. 186: 2051 2056.
92. Yamamoto, M.,, S. Sato,, K. Mori,, O. Takeuchi,, K. Hoshino,, K. Takeda,, and S. Akira. 2002. A novel TIR domain-containing adaptor that preferentially activates the interferon-β promoter. J. Immunol. 169: 6668 6672.
93. Yamamoto, M.,, S. Sato,, H. Hemmi,, H. Sanjo,, S. Uematsu,, T. Kaisho,, K. Hoshino,, O. Takeuchi,, M. Kobayashi,, T. Fujita,, K. Takeda,, and S. Akira. 2002. Essential role of TIRAP/Mal for activation of the signaling cascade shared by TLR2 and TLR4. Nature 420: 324 329.
94. Yoneyama, M.,, W. Suhara,, Y. Fukuhara,, M. Fukuda,, E. Nishida,, and T. Fujita. 1998. 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.
95. Yoshimura, A.,, E. Lien,, R. R. Ingalls,, E. Tuomanen,, R. Dziarski,, and D. Golenbock. 1999. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 165: 1 5.
96. Zhang, G.,, and S. Ghosh. 2002. Negative regulation of toll-like receptor-mediated signaling by Tollip. J. Biol. Chem. 77: 7059 7065.

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