Molecular Medicine

, Volume 14, Issue 5–6, pp 346–352 | Cite as

Functional Consequences of Toll-like Receptor 4 Polymorphisms

  • Bart Ferwerda
  • Matthew B. B. McCall
  • Karlijn Verheijen
  • Bart-Jan Kullberg
  • André J. A. M. van der Ven
  • Jos W. M. Van der Meer
  • Mihai G. Netea
Review Article


Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that recognizes mainly lipopolysaccharide (LPS) of Gram-negative bacteria, but also structures from fungal and mycobacterial pathogens, as well as endogenous ligands. Two nonsynonymous polymorphisms of TLR4, Asp299Gly and Thr399lle, have been suggested to alter the function of the receptor. Some, but not all, studies have proposed that these polymorphisms lead to reduced cytokine response and increased susceptibility to Gram-negative infections. In this review, we compare studies that assessed the effect of the Asp299Gly and Thr399lle polymorphisms on susceptibility to Gram-negative infections and examine the phenotypic consequences of these polymorphisms. In addition, we review the geographical distribution of TLR4 polymorphisms and present a model for evolutionary pressures on the TLR4 genetic make-up.


  1. 1.
    Akira S, Hemmi H. (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol. Lett. 85:85–95.CrossRefPubMedGoogle Scholar
  2. 2.
    Medzhitov R, Janeway C Jr. (2000) Innate immunity. N. Engl. J. Med. 343:338–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Kawai T, Akira S. (2006) TLR signaling. Cell Death Differ. 13:816–25.CrossRefPubMedGoogle Scholar
  4. 4.
    Yarovinsky F, et al. (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Zhang D, et al. (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Takeda K, Kaisho T, Akira S. (2003) Toll-like receptors. Annu. Rev. Immunol. 21:335–76.CrossRefGoogle Scholar
  7. 7.
    Hashimoto C, Hudson KL, Anderson KV. (1988) The Toll gene of Drosophila, required for dorsalventral embryonic polarity, appears to encode a transmembrane protein. Cell 52:269–79.CrossRefPubMedGoogle Scholar
  8. 8.
    Hoffmann JA. (2003) The immune response of Drosophila. Nature 426:33–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–83.CrossRefGoogle Scholar
  10. 10.
    Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF. (1998) A family of human receptors structurally related to Drosophila Toll. Proc. Natl. Acad. Sci. U. S. A. 95:588–93.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–7.CrossRefGoogle Scholar
  12. 12.
    Sultzer BM. (1969) Genetic factors in leucocyte responses to endotoxin: further studies in mice. J Immunol 103:32–8.PubMedGoogle Scholar
  13. 13.
    Sultzer BM. (1968) Genetic control of leucocyte responses to endotoxin. Nature 219:1253–4.CrossRefPubMedGoogle Scholar
  14. 14.
    Poltorak A, et al. (1998) Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis. 24:340–55.CrossRefPubMedGoogle Scholar
  15. 15.
    Poltorak A, et al. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–8.CrossRefGoogle Scholar
  16. 16.
    Schumann RR, et al. (1990) Structure and function of lipopolysaccharide binding protein. Science 249:1429–31.CrossRefPubMedGoogle Scholar
  17. 17.
    Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC. (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431–3.CrossRefGoogle Scholar
  18. 18.
    Fenton MJ, Golenbock DT. (1998) LPS-binding proteins and receptors. J. Leukoc. Biol. 64:25–32.CrossRefPubMedGoogle Scholar
  19. 19.
    O’Neill LA, Greene C. (1998) Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukoc. Biol. 63:650–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Kim HM, et al. (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–17.CrossRefPubMedGoogle Scholar
  21. 21.
    Akira S, Takeda K. (2004) Toll-like receptor signaling. Nat. Rev. Immunol. 4:499–511.CrossRefPubMedGoogle Scholar
  22. 22.
    O’Neill LA, Bowie AG. (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signaling. Nat. Rev. Immunol. 7:353–64.CrossRefPubMedGoogle Scholar
  23. 23.
    Vogel SN, Fitzgerald KA, Fenton MJ. (2003) TLRs: differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol. Interv. 3:466–77.CrossRefPubMedGoogle Scholar
  24. 24.
    Miggin SM, O’Neill LA. (2006) New insights into the regulation of TLR signaling. J. Leukoc. Biol. 80: 220–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Mushegian A, Medzhitov R. (2001) Evolutionary perspective on innate immune recognition. J. Cell Biol. 155:705–10.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B. (2000) Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4). Genome Biol. 1:RESEARCH002.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Smirnova I, Hamblin MT, McBride C, Beutler B, Di RA. (2001) Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans. Genetics 158:1657–64.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Arbour NC, et al. (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. 25:187–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Schröder NW, Schumann RR. (2005) Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect. Dis. 5:156–64.CrossRefPubMedGoogle Scholar
  30. 30.
    Ferwerda B, et al. (2007) TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc. Natl. Acad. Sci. U. S. A. 104:16645–50.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Dahmer MK, Randolph A, Vitali S, Quasney MW. (2005) Genetic polymorphisms in sepsis. Pediatr. Crit. Care Med. 6:S61–73.CrossRefGoogle Scholar
  32. 32.
    Read RC, Wyllie DH. (2001) Toll receptors and sepsis. Curr. Opin. Crit. Care 7:371–5.CrossRefPubMedGoogle Scholar
  33. 33.
    Pasterkamp G, van Keulen JK, de Kleijn DP. (2004) Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease. Eur. J. Clin. Invest. 34:328–34.CrossRefPubMedGoogle Scholar
  34. 34.
    Vink A, de Kleijn DP, Pasterkamp G. (2004) Functional role for Toll-like receptors in atherosclerosis and arterial remodeling. Curr. Opin. Lipidol. 15:515–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Yang IA, Fong KM, Holgate ST, Holloway JW. (2006) The role of Toll-like receptors and related receptors of the innate immune system in asthma. Curr. Opin. Allergy Clin. Immunol. 6:23–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Van der Graaf CA, Netea MG, Drenth IP, te Morsche RH, Van der Meer JW, Kullberg BJ. (2003) Candida-specific interferon-gamma deficiency and Toll-like receptor polymorphisms in patients with chronic mucocutaneous candidiasis. Neth. J. Med. 61:365–9.PubMedGoogle Scholar
  37. 37.
    Van der Graaf CA, et al. (2006) Toll-like receptor 4 Asp299Gly/Thr399Ile polymorphisms are a risk factor for Candida bloodstream infection. Eur. Cytokine Netw. 17:29–34.PubMedGoogle Scholar
  38. 38.
    Brett PM, et al. (2005) Functional gene polymorphisms in aggressive and chronic periodontitis. J. Dent. Res. 84:1149–53.CrossRefPubMedGoogle Scholar
  39. 39.
    Folwaczny M, Glas J, Torok HP, Limbersky O, Folwaczny C. (2004) Toll-like receptor (TLR) 2 and 4 mutations in periodontal disease. Clin. Exp. Immunol. 135:330–5.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Schröder NW, et al. (2005) Chronic periodontal disease is associated with single-nucleotide polymorphisms of the human TLR-4 gene. Genes Immun. 6:448–51.CrossRefPubMedGoogle Scholar
  41. 41.
    Inoue Y, et al. (2007) CD14-550 C/T, which is related to the serum level of soluble CD14, is associated with the development of respiratory syncytial virus bronchiolitis in the Japanese population. J. Infect. Dis. 195:1618–24.CrossRefPubMedGoogle Scholar
  42. 42.
    Paulus SC, Hirschfeld AF, Victor RE, Brunstein J, Thomas E, Turvey SE. (2007) Common human Toll-like receptor 4 polymorphisms: role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin. Immunol. 123:252–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Puthothu B, Forster J, Heinzmann A, Krueger M. (2006) TLR-4 and CD14 polymorphisms in respiratory syncytial virus associated disease. Dis. Markers 22:303–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Cervera C, et al. (2007) The influence of innate immunity gene receptors polymorphisms in renal transplant infections. Transplantation 83:1493–500.CrossRefPubMedGoogle Scholar
  45. 45.
    Ducloux D, et al. (2005) Relevance of Toll-like receptor-4 polymorphisms in renal transplantation. Kidney Int. 67:2454–61.CrossRefPubMedGoogle Scholar
  46. 46.
    Lorenz E, et al. (2001) Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 7:384–7.CrossRefPubMedGoogle Scholar
  47. 47.
    Palmer SM, et al. (2006) Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation. Clin. Transplant. 20:30–6.CrossRefPubMedGoogle Scholar
  48. 48.
    de Ridder L, et al. (2007) Genetic susceptibility has a more important role in pediatric-onset Crohn’s disease than in adult-onset Crohn’s disease. Inflamm. Bowel Dis. 13:1083–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Figueroa C, et al. (2006) NOD2/CARD15 and Toll-like 4 receptor gene polymorphism in Chilean patients with inflammatory bowel disease. Eur. Cytokine Netw. 17:125–30.PubMedGoogle Scholar
  50. 50.
    Ouburg S, et al. (2005) The Toll-like receptor 4 (TLR4) Asp299Gly polymorphism is associated with colonic localisation of Crohn’s disease without a major role for the Saccharomyces cerevisiae mannan-LBP-CD14-TLR4 pathway. Gut 54:439–40.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Peeters H, et al. (2007) CARD15 variants determine a disturbed early response of monocytes to adherent-invasive Escherichia coli strain LF82 in Crohn’s disease. Int. J. Immunogenet. 34:181–91.CrossRefPubMedGoogle Scholar
  52. 52.
    Awomoyi AA, et al. (2007) Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J. Immunol. 179:3171–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Chanock SJ, et al. (2007) Replicating genotype-phenotype associations. Nature 447:655–60.CrossRefPubMedGoogle Scholar
  54. 54.
    Schwartz DA. (2001) The role of TLR4 in endotoxin responsiveness in humans. J. Endotoxin Res. 7:389–93.CrossRefPubMedGoogle Scholar
  55. 55.
    Schwartz DA. (2001) Inhaled endotoxin, a risk for airway disease in some people. Respir. Physiol. 128:47–55.CrossRefPubMedGoogle Scholar
  56. 56.
    Schwartz DA. (2002) The genetics of innate immunity. Chest 121:62S–8S.CrossRefPubMedGoogle Scholar
  57. 57.
    Calvano JE, et al. (2006) Response to systemic endotoxemia among humans bearing polymorphisms of the Toll-like receptor 4 (hTLR4). Clin. Immunol. 121:186–90.CrossRefPubMedGoogle Scholar
  58. 58.
    Marsik C, Jilma B, Joukhadar C, Mannhalter C, Wagner O, Endler G. (2005) The Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms influence the late inflammatory response in human endotoxemia. Clin. Chem. 51:2178–80.CrossRefPubMedGoogle Scholar
  59. 59.
    Schippers EF, van’t Veer C, van Voorden S, Martina CA, le Cessie S, van Dissel JT. (2004) TNF-alpha promoter, Nod2 and Toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine 26:16–24.CrossRefPubMedGoogle Scholar
  60. 60.
    Schippers EF, et al. (2005) IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine 29:215–28.CrossRefPubMedGoogle Scholar
  61. 61.
    Mockenhaupt FP, et al. (2006) Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. J. Commun. Dis. 38:230–45.PubMedGoogle Scholar
  62. 62.
    Newport MJ, et al. (2004) The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis (Edinb.) 84:347–52.CrossRefGoogle Scholar
  63. 63.
    Lorenz E, Mira JP, Frees KL, Schwartz DA. (2002) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch. Intern. Med. 162:1028–32.CrossRefPubMedGoogle Scholar
  64. 64.
    Rallabhandi P, et al. (2006) Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J. Immunol. 177:322–32.CrossRefPubMedGoogle Scholar
  65. 65.
    Kumpf O, Hamann L, Schlag PM, Schumann RR. (2006) Pre- and postoperative cytokine release after in vitro whole blood lipopolysaccharide stimulation and frequent Toll-like receptor 4 polymorphisms. Shock 25:123–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Heesen M, Bloemeke B, Kunz D. (2003) The cytokine synthesis by heterozygous carriers of the Toll-like receptor 4 Asp299Gly polymorphism does not differ from that of wild type homozygotes. Eur. Cytokine Netw. 14:234–7.PubMedGoogle Scholar
  67. 67.
    von Aulock S, et al. (2003) Heterozygous toll-like receptor 4 polymorphism does not influence lipopolysaccharide-induced cytokine release in human whole blood. J. Infect. Dis. 188:938–43.CrossRefGoogle Scholar
  68. 68.
    Chang JH, Hampartzoumian T, Everett B, Lloyd A, McCluskey PJ, Wakefield D. (2007) Changes in Toll-like receptor (TLR)-2 and TLR4 expression and function but not polymorphisms are associated with acute anterior uveitis. Invest. Ophthalmol. Vis. Sci 48:1711–7.CrossRefPubMedGoogle Scholar
  69. 69.
    Tiberio L, Fletcher L, Eldridge JH, Duncan DD. (2004) Host factors impacting the innate response in humans to the candidate adjuvants RC529 and monophosphoryl lipid A. Vaccine 22:1515–23.CrossRefPubMedGoogle Scholar
  70. 70.
    Kroner A, et al. (2005) Impact of the Asp299Gly polymorphism in the Toll-like receptor 4 (TLR-4) gene on disease course of multiple sclerosis. J. Neuroimmunol. 165:161–5.CrossRefPubMedGoogle Scholar
  71. 71.
    van der Graaf C, et al. (2005) Functional consequences of the Asp299Gly Toll-like receptor-4 polymorphism. Cytokine 30:264–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Fagerås BM, et al. (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J. Allergy Clin. Immunol. 114:561–7.CrossRefGoogle Scholar
  73. 73.
    Erridge C, Stewart J, Poxton IR. (2003) Monocytes heterozygous for the Asp299Gly and Thr399Ile mutations in the Toll-like receptor 4 gene show no deficit in lipopolysaccharide signaling. J. Exp. Med. 197:1787–91.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Schmitt C, Humeny A, Becker CM, Brune K, Pahl A. (2002) Polymorphisms of TLR4: rapid genotyping and reduced response to lipopolysaccharide of TLR4 mutant alleles. Clin. Chem. 48:1661–7.PubMedGoogle Scholar
  75. 75.
    Norata GD, et al. (2005) Effect of the Toll-like receptor 4 (TLR-4) variants on intima-media thickness and monocyte-derived macrophage response to LPS. J. Intern. Med. 258:21–7.CrossRefPubMedGoogle Scholar
  76. 76.
    Montes AH, et al. (2006) The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis. Clin. Exp. Immunol. 143:404–13.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Kinane DF, et al. (2006) Gingival epithelial cells heterozygous for Toll-like receptor 4 polymorphisms Asp299Gly and Thr399ile are hypo-responsive to Porphyromonas gingivalis. Genes Immun. 7:190–200.CrossRefPubMedGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Bart Ferwerda
    • 1
    • 2
  • Matthew B. B. McCall
    • 1
    • 3
  • Karlijn Verheijen
    • 1
    • 2
  • Bart-Jan Kullberg
    • 1
    • 2
  • André J. A. M. van der Ven
    • 1
    • 2
  • Jos W. M. Van der Meer
    • 1
    • 2
  • Mihai G. Netea
    • 1
    • 2
  1. 1.Department of Internal MedicineRadboud University Nijmegen Medical CenterNijmegenThe Netherlands
  2. 2.Nijmegen University Center for Infectious DiseasesNijmegenThe Netherlands
  3. 3.Department of ParasitologyNijmegenThe Netherlands

Personalised recommendations