Toll-like Receptors: Implication in Human Disease

  • S. Gibot
  • J. P. Mira
  • A. Mebazaa
Part of the Yearbook of Intensive Care and Emergency Medicine 2001 book series (YEARBOOK, volume 2001)

Abstract

The innate immune system includes macrophages and natural killer (NK) cells, which may act directly on the pathogen or, by releasing cytokines and expressing other stimulatory molecules, trigger adaptative immune response by activating T and B cells. The strategy of the innate immune response may not be to recognize every single antigen, but rather to focus on few, highly conserved structures which are referred to as pathogen-associated molecular patterns (PAMPs). The receptors of the innate immune system that have evolved to recognize the PAMPs are called pattern-recognition receptors (Table 1). These activate signal-transduction pathways that induce the expression of a variety of immune-response genes, including inflammatory cytokines [1]. The recently identified receptors of the Toll family appear to have a major role in the induction of immune and inflammatory responses. Two discoveries support this role: the implication of the Toll-like receptors (TLRs) in innate immunity in Drosophila [2], and the identification of a TLR homolog as the gene responsible for lipopolysaccharide (LPS) responses in two natural mouse mutants [3,4].

Keywords

Cysteine Serine Cardiomyopathy Kelly Mannose 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Janeway CA Jr, Medzhitov R (1998) Introduction: the role of innate immunity in the adaptative immune response. Semin Immunol 10:349–350PubMedCrossRefGoogle Scholar
  2. 2.
    Lemaitre B, Nicolas E, Michaut L, et al (1996) The dorsoventral regulatory gene cassette spaet-zle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983PubMedCrossRefGoogle Scholar
  3. 3.
    Poltorak A, He X, Smirnova I, et al (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tir 4 gene. Science 282:2085–2088PubMedCrossRefGoogle Scholar
  4. 4.
    Qureshi ST, Larivière L, Leveque G, et al (1999) Endotoxin-tolerant mice have mutations in Tlr4. J Exp Med 189:615–625PubMedCrossRefGoogle Scholar
  5. 5.
    Rock FL, Hardiman G, Timans JC, et al (1998) A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 95:588–593PubMedCrossRefGoogle Scholar
  6. 6.
    Medzhitov R, Preston-Hulburt P, Janeway GA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptative immunity. Nature 395:384–388Google Scholar
  7. 7.
    Chaudhary PM, Fergusson C, Nguyen V, et al (1998) Cloning and characterization of two Toll/interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family inhumans. Blood 91:4020–4033PubMedGoogle Scholar
  8. 8.
    Takeuchi O, Kawai T, Sanjo H, et al (1999) A novel member of an expending toll-like receptor family. Gene 231–259Google Scholar
  9. 9.
    Hoshino K, Takeuchi O, Kawai T, et al (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence of the Tlr4 as the Lps gene product. J Immunol 162:3749–3752PubMedGoogle Scholar
  10. 10.
    Takeuchi O, Hoshino K, Kawai T, et al (1999) Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11:443–451PubMedCrossRefGoogle Scholar
  11. 11.
    Underbill DM, Ozinsky A, Hajjar AM, et al (1999) The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401:811–815CrossRefGoogle Scholar
  12. 12.
    Arbour NC, Lorenz E, Schutte BC, et al (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191PubMedCrossRefGoogle Scholar
  13. 13.
    Shimazu R, Akashi S, Ogata H, et al (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782PubMedCrossRefGoogle Scholar
  14. 14.
    Akashi S, Ogata H, Kirikae F, et al (2000) Regulatory roles for CD 14 and phosphatidylinositol in the signalling via Toll-like receptor 4-MD-2. Biochem Biophys Res Comm 268:172–177PubMedCrossRefGoogle Scholar
  15. 15.
    Staege H, Schaffner A, Schneemann M (2000) Human Toll-like receptor 2 and 4 are targets for deactivation of mononuclear phagocytes by IL-4. Immunol Lett 71:1–3PubMedCrossRefGoogle Scholar
  16. 16.
    Volk HD, Reinke P, Krausch D, et al (1996) Monocyte deactivation-rationale for a new therapeutic strategy in sepsis. Intensive Care Med 22: S474–S481PubMedCrossRefGoogle Scholar
  17. 17.
    Lorenz E, Mira JP, Cornish KL, et al (2000) A novel polymorphism in the Toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68:6398–6401PubMedCrossRefGoogle Scholar
  18. 18.
    Kelly RA, Smith TW (1997) Cytokines and cardiac contractile functions. Circulation 95:778–781PubMedGoogle Scholar
  19. 19.
    Bristow MR (1998) Tumor necrosis factor-alpha and cardiomyopathy. Circulation 97:1340–1341PubMedGoogle Scholar
  20. 20.
    Frantz S, Kobzik L, Kim YD, et al (1999) Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 104:271–280PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2001

Authors and Affiliations

  • S. Gibot
  • J. P. Mira
  • A. Mebazaa

There are no affiliations available

Personalised recommendations