Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

TLR4, Toll-Like Receptor 4

  • Jayalakshmi Krishnan
  • Sangdun Choi
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_592

Synonyms

Historical Background

Overproduction of the cytokine profile (cytokine tsunami or storm) can be caused by both infectious and non-infectious diseases. During this process, inflammatory responses are activated either to provide a protective mechanism or to damage tissues when excessively produced cytokines attempt to overwhelm the cause of their production. This system is activated whenever there is a foreign invasion of the body. Foreign invasion is attributed to microbial associated molecules known as Pathogen Associated Molecular Patterns (PAMPS), which activate our immune system through Pattern Recognition Receptors (PRRs) present in the body fluids, cell membranes, and cytoplasm. PRRs not only identify PAMPs, but also molecules released from damaged cells known as Damage Associated Molecular Patterns (DAMPs). There is a great deal of evidence that DAMPs...

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Notes

Acknowledgments

This work was supported by the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (2012016803).

References

  1. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 1998;9:143–50.PubMedGoogle Scholar
  2. Anderson KV, Jurgens G, Nusslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell. 1985;42:779–89.PubMedGoogle Scholar
  3. Baldridge JR, McGowan P, Evans JT, Cluff C, Mossman S, et al. Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol Ther. 2004;4:1129–38.PubMedGoogle Scholar
  4. Beutler B. Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev. 2009;227:248–63.PubMedGoogle Scholar
  5. Czeslick E, Struppert A, Simm A, Sablotzki A. E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes. Inflamm Res. 2006;55:511–5.PubMedGoogle Scholar
  6. Douville RN, Lissitsyn Y, Hirschfeld AF, Becker AB, Kozyrskyj AL, et al. TLR4 Asp299Gly and Thr399Ile polymorphisms: no impact on human immune responsiveness to LPS or respiratory syncytial virus. PLoS One. 2010;5:e12087.PubMedGoogle Scholar
  7. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003;198:1043–55.PubMedGoogle Scholar
  8. Gay NJ, Gangloff M. Structure and function of Toll receptors and their ligands. Annu Rev Biochem. 2007;76:141–65.PubMedGoogle Scholar
  9. Gay NJ, Keith FJ. Drosophila Toll and IL-1 receptor. Nature. 1991;351:355–6.PubMedGoogle Scholar
  10. Halfon MS, Hashimoto C, Keshishian H. The Drosophila toll gene functions zygotically and is necessary for proper motoneuron and muscle development. Dev Biol. 1995;169:151–67.PubMedGoogle Scholar
  11. Hansson GK, Edfeldt K. Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol. 2005;25:1085–7.PubMedGoogle Scholar
  12. Hashiguchi S, Yamaguchi Y, Takeuchi O, Akira S, Sugimura K. Immunological basis of M13 phage vaccine: Regulation under MyD88 and TLR9 signaling. Biochem Biophys Res Commun. 2010;402:19–22.PubMedGoogle Scholar
  13. Hosoi T, Yokoyama S, Matsuo S, Akira S, Ozawa K. Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PLoS One. 2010;5:e12537.PubMedGoogle Scholar
  14. Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–49.PubMedGoogle Scholar
  15. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, et al. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007;130:1071–82.PubMedGoogle Scholar
  16. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity. 1999;11:115–22.PubMedGoogle Scholar
  17. Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006;13:816–25.PubMedGoogle Scholar
  18. Kawai T, Akira S. The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol. 2009;21:317–37.PubMedGoogle Scholar
  19. Kim HM, Park BS, Kim JI, Kim SE, Lee J, et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell. 2007;130:906–17.PubMedGoogle Scholar
  20. Kundi M. New hepatitis B vaccine formulated with an improved adjuvant system. Expert Rev Vaccines. 2007;6:133–40.PubMedGoogle Scholar
  21. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83.PubMedGoogle Scholar
  22. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, et al. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science. 2008;320:379–81.PubMedGoogle Scholar
  23. Loiarro M, Gallo G, Fanto N, De Santis R, Carminati P, et al. Identification of critical residues of the MyD88 death domain involved in the recruitment of downstream kinases. J Biol Chem. 2009;284:28093–103.PubMedGoogle Scholar
  24. McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, et al. Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci USA. 2006;103:9196–201.PubMedGoogle Scholar
  25. Medzhitov R, Preston-Hurlburt P, Janeway Jr CA. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7.PubMedGoogle Scholar
  26. Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, et al. Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther. 2003;304:1093–102.PubMedGoogle Scholar
  27. Nishitani C, Mitsuzawa H, Hyakushima N, Sano H, Matsushima N, et al. The Toll-like receptor 4 region Glu24-Pro34 is critical for interaction with MD-2. Biochem Biophys Res Commun. 2005;328:586–90.PubMedGoogle Scholar
  28. Ohnishi H, Tochio H, Kato Z, Orii KE, Li A, et al. Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling. Proc Natl Acad Sci USA. 2009;106:10260–5.PubMedGoogle Scholar
  29. O'Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–64.PubMedGoogle Scholar
  30. Papadopoulos AI, Ferwerda B, Antoniadou A, Sakka V, Galani L, et al. Association of toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms with increased infection risk in patients with advanced HIV-1 infection. Clin Infect Dis. 2010;51:242–7.PubMedGoogle Scholar
  31. Park BS, Song DH, Kim HM, Choi BS, Lee H, et al. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature. 2009;458:1191–5.PubMedGoogle Scholar
  32. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8.PubMedGoogle Scholar
  33. Przetak M, Chow J, Cheng H, Rose J, Hawkins LD, et al. Novel synthetic LPS receptor agonists boost systemic and mucosal antibody responses in mice. Vaccine. 2003;21:961–70.PubMedGoogle Scholar
  34. Rose D, Zhu X, Kose H, Hoang B, Cho J, et al. Toll, a muscle cell surface molecule, locally inhibits synaptic initiation of the RP3 motoneuron growth cone in Drosophila. Development. 1997;124:1561–71.PubMedGoogle Scholar
  35. Rossignol DP, Wong N, Noveck R, Lynn M. Continuous pharmacodynamic activity of eritoran tetrasodium, a TLR4 antagonist, during intermittent intravenous infusion into normal volunteers. Innate Immun. 2008;14:383–94.PubMedGoogle Scholar
  36. Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, et al. The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci USA. 2006;103:6299–304.PubMedGoogle Scholar
  37. Schaefer L. Extracellular matrix molecules: endogenous danger signals as new drug targets in kidney diseases. Curr Opin Pharmacol. 2010;10:185–90.PubMedGoogle Scholar
  38. Schmitt C, Humeny A, Becker CM, Brune K, Pahl A. Polymorphisms of TLR4: rapid genotyping and reduced response to lipopolysaccharide of TLR4 mutant alleles. Clin Chem. 2002;48:1661–7.PubMedGoogle Scholar
  39. Schnare M, Holt AC, Takeda K, Akira S, Medzhitov R. Recognition of CpG DNA is mediated by signaling pathways dependent on the adaptor protein MyD88. Curr Biol. 2000;10:1139–42.PubMedGoogle Scholar
  40. Schroder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005;5:156–64.PubMedGoogle Scholar
  41. Seo SU, Kwon HJ, Song JH, Byun YH, Seong BL, et al. MyD88 signaling is indispensable for primary influenza A virus infection but dispensable for secondary infection. J Virol. 2010;84:12713–22.PubMedGoogle Scholar
  42. Thompson BS, Chilton PM, Ward JR, Evans JT, Mitchell TC. The low-toxicity versions of LPS, MPL adjuvant and RC529, are efficient adjuvants for CD4+ T cells. J Leukoc Biol. 2005;78:1273–80.PubMedGoogle Scholar
  43. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009;461:114–9.PubMedGoogle Scholar
  44. Xu Y, Tao X, Shen B, Horng T, Medzhitov R, et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature. 2000;408:111–5.PubMedGoogle Scholar
  45. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301:640–3.PubMedGoogle Scholar
  46. Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA. 2010;107:11942–7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Molecular Science and TechnologyAjou UniversitySuwonSouth Korea