Advertisement

Toll-Like Receptors

  • Gyongyi SzaboEmail author
  • Pranoti Mandrekar
Chapter

Abstract

Since the discovery of toll-like receptors (TLRs) in ­Dro­sophila in 1996 [1], scientific knowledge has exploded on the role of pattern recognition receptors in immunity, host defense, and in various noninfectious conditions including liver diseases. Studies demonstrated that TLR expression in immune and nonimmune cells plays an important role in tissue homeostasis, response to infections, and injury in the liver. Links between TLR activation and modulation of functions of TLRs in liver diseases are being discovered. Here, we discuss the characteristics and signaling pathways of TLRs and summarize current knowledge on their role in liver diseases.

Keywords

Kupffer Cell Alcoholic Hepatitis TLR4 Activation Biliary Epithelial Cell TLR4 Coreceptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spaetzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefPubMedGoogle Scholar
  2. 2.
    Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14CrossRefPubMedGoogle Scholar
  3. 3.
    Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32CrossRefPubMedGoogle Scholar
  4. 4.
    Yamamoto M, Akira S (2005) TIR domain-containing adaptors regulate TLR signaling pathways. Adv Exp Med Biol 560:1–9CrossRefPubMedGoogle Scholar
  5. 5.
    Jin MS, Lee J-O (2008) Structures of TLR-ligand complexes. Curr Opin Immunol 20:414–418CrossRefPubMedGoogle Scholar
  6. 6.
    Beutler B, Poltorak A (2001) Sepsis and evolution of the innate immune response. Crit Care Med 29:S2–S7CrossRefGoogle Scholar
  7. 7.
    Beutler B (2002) LPS in microbial pathogenesis: promise and fulfillment. J Endotoxin Res 8:329–335PubMedGoogle Scholar
  8. 8.
    Koyama S, Ishii K, Coban C, Akira S (2008) Innate immune response to viral infection. Cytokine 43:336–341CrossRefPubMedGoogle Scholar
  9. 9.
    Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR (2006) Emerging paradigm: toll-like receptor 4-­sentinel for the detection of tissue damage. Shock 28: 430–437CrossRefGoogle Scholar
  10. 10.
    O’Neill LA, Bowie AG (2007) The family of five: TIR:domain-containing adaptors in Toll-like receptor signaling. Nat Rev Immunol 7:353–364CrossRefPubMedGoogle Scholar
  11. 11.
    Kawai T, Akira S (2007) Signaling to NF-κB by Toll-like receptors. Trends Mol Med 13:460–469CrossRefPubMedGoogle Scholar
  12. 12.
    Vogel SN, Fitzgerald KA, Fenton MJ (2003) TLRs: differential adaptor utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv 3: 466–477CrossRefPubMedGoogle Scholar
  13. 13.
    Kawai T, Takeuchi O, Fujita T, Inoue JI, Muhlradt PF, Sato S, Hoshino K et al (2001) Lipopolysaccharide-inducible genes. J Immunol 167:5887–5894PubMedGoogle Scholar
  14. 14.
    Fitzgerald KA, Rowe DC, Barnes BJ, Caffey DR, Vinistin A, Latz E, Monks B, Golenbock D (2003) LPS-TLR4 signaling to IRFE/7 and NF-κB involves the adaptors TRAM and TRIF. J Exp Med 198:1043–1045CrossRefPubMedGoogle Scholar
  15. 15.
    Beg AA, Baldwin AS (1993) The IκB proteins: multifunctional regulators of Rel/NFκB transcription factors. Genes Dev 7:2064–2070CrossRefPubMedGoogle Scholar
  16. 16.
    Doyle SL, Oneill LA (2006) TLRs: from discovery of NF-κB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72:1102–1113CrossRefPubMedGoogle Scholar
  17. 17.
    O’Neill LA (2008) When signaling pathways collide: positive and negative regulation of Toll-like receptor signal transduction. Immunity 29:12–20CrossRefPubMedGoogle Scholar
  18. 18.
    Lu Y-C, Yeh W-C, Ohashi PS (2008) LPS/TLR4 signal transduction pathway. Cytokine 42:145–151CrossRefPubMedGoogle Scholar
  19. 19.
    Lang T, Mansell A (2007) The negative regulation of Toll-like receptor and associated pathways. Immunol Cell Biol 85:425–434CrossRefPubMedGoogle Scholar
  20. 21.
    Szabo G, Dolganiuc A, Mandrekar P (2006) Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 44:287–298CrossRefPubMedGoogle Scholar
  21. 22.
    Vodovotz Y, Liu S, McCloskey C, Shapiro R, Green A, Billiar TR (2001) The hepatocyte as a microbial product-responsive cell. J Endotoxin Res 7:365–373PubMedGoogle Scholar
  22. 23.
    Ojaniemi M, Liljeroos M, Harju K, Sormunen R, Vuolteenaho R, Hallman M (2006) TLR-2 is upregulated and mobilized to the hepatocyte plasma membrane in the space of Disse and to the Kupffer cells TLR-4 dependently during acute endotoxemia in mice. Immunol Lett 102: 158–168CrossRefPubMedGoogle Scholar
  23. 24.
    Jiang W, Sun R, Wei H, Tian Z (2005) Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-­regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci U S A 102:17077–17082CrossRefPubMedGoogle Scholar
  24. 25.
    Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG (1994) Inactivation of Kuppfer cells prevents early alcohol-induced liver injury. Hepatology 20:453–460CrossRefPubMedGoogle Scholar
  25. 26.
    Sumpter TL, Abe M, Tokita D, Thompson AW (2007) Dendritic cells, the liver and transplantation. Hepatology 46: 2021–2031CrossRefPubMedGoogle Scholar
  26. 27.
    Sawaki J, Tsutsui H, Hayashi N, Yasuda K, Akira S, Tanizawa T et al (2007) Type I cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways. Int Immunol 19:311–320CrossRefPubMedGoogle Scholar
  27. 28.
    Liu S, Gallo DJ, Green AM, Williams DL, Gong X, Shapiro RA, Gambotto AA, Humphris EL, Vodovotz Y, Billiar TR (2002) Role of toll-like receptors in changes in gene expression and NF-κB activation in mouse hepatocytes stimulated with lipopolysaccharide. Infect Immun 70: 3433–3442CrossRefPubMedGoogle Scholar
  28. 29.
    Matsumura T, Degawa T, Takii T, Hayashi H, Okamoto T, Inoue J et al (2003) TRAF6-NF-κB pathway is essential for interleukin-1-induces TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes. Immunology 109:127–136CrossRefPubMedGoogle Scholar
  29. 30.
    Li K, Chen Z, Kato N, Gale M Jr, Lemon SM (2005) Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes. J Biol Chem 280:16739–16747CrossRefPubMedGoogle Scholar
  30. 31.
    Urig A, Banafsche R, Kremer M, Hegenbarth S, Hamann A, Neurath M, Gerken G et al (2005) Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J Leukoc Biol 77:626–633CrossRefGoogle Scholar
  31. 32.
    Harada K, Isse K, Nakanuma Y (2006) Interferon (gamma) accelerates NF-(kappa) B activation of biliary epithelial cells induced by Toll-like receptor and ligand interactin. J Clin Pathol 59:184–190CrossRefPubMedGoogle Scholar
  32. 33.
    Harada K, Isse K, Sato Y, Ozaki S, Nakanuma Y (2006) Endotoxin tolerance in human intraheptatic biliary epithelial cells is induced by upregulation of IRAK-M. Liver Int 26: 935–942CrossRefPubMedGoogle Scholar
  33. 34.
    Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA (2003) Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37:1043–1055CrossRefPubMedGoogle Scholar
  34. 35.
    Brun P, Castagliuolo I, Pinzani M, Palu G, Martines D (2005) Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 289:G571–G578CrossRefGoogle Scholar
  35. 36.
    Seki E, DeMinicis S, Osterreicher CH, Klue J, Osawa Y, Brenner DA et al (2007) TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 13:1324–1332CrossRefPubMedGoogle Scholar
  36. 37.
    Chen Z, Cheng Y, Xu Y, Liao J, Zhang X, Hu Y, Zhang Q et al (2008) Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol. 128:400–408CrossRefPubMedGoogle Scholar
  37. 38.
    Isogawa M, Robek MD, Furuichi Y, Chisari FV (2005) Toll-like receptor receptor signaling inhibits hepatitis B virus replication in vivo. J Virol 79:7269–7722CrossRefPubMedGoogle Scholar
  38. 39.
    McClary H, Chisari KR, FV GLG (2000) Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines. J Virol 74:2255–2264CrossRefPubMedGoogle Scholar
  39. 40.
    Ito T, Amakawa R, Fukuhara S (2002) Roles of Toll-like receptors in natural interferon-producing cells as sensors in immune surveillance. Hum Immunol 63:1120–1125CrossRefPubMedGoogle Scholar
  40. 41.
    Szabo G, Dolganiuc A (2007) The role of plasmacytoid dendritic cell-derived IFNα in antiviral immunity. Crit Rev Immunol 28:61–94Google Scholar
  41. 42.
    Verthelyi D, Wang VW, Lifson JD, Klinman DM (2004) CpG oligodeoxynucleotides improve the response to hepatitis B immunization in healthy and SIV-infected rhesus macaues. AIDS 18:1003–1008CrossRefPubMedGoogle Scholar
  42. 43.
    Otsuka M, Kato N, Moriyama M, Taniguchi H, Wang Y, Dharel N, Kawabe T et al (2005) Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses. Hepatology 41:1004–1012CrossRefPubMedGoogle Scholar
  43. 44.
    Li K, Foy E, Ferron JC, Nakamura M, Ferreon AC, Ikeda M, Ray Sc et al (2005) Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci USA 102: 2992–2997CrossRefPubMedGoogle Scholar
  44. 45.
    Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, Szabo G (2006) HCV Core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 177:6758–6768PubMedGoogle Scholar
  45. 46.
    Dolganiuc A, Oak S, Kodys K, Golenbock DT, Finberg RW, Kurt-Jones E, Szabo G (2004) Hepatitis C core and nonstructural 3 protein trigger toll-like receptor 2-mediated path­ways and inflammatory activation. Gastroenterology 127: 1513–1524CrossRefPubMedGoogle Scholar
  46. 47.
    Visvanathan K, Skinner M, Chang J, Lewin S, Thompson A, Locarnini S, Riordan SM (2005) Up-regulation of Toll-like receptors expression in chronic hepatitis C: correlation with circulating pro-inflammatory cytokine levels and hepatic necro-inflammatory activity. Hepatology 42:547AGoogle Scholar
  47. 48.
    Dolganiuc A, Norkina O, Kodys K, Catalano D, Mandrekar P, Bakis G, Marshall C, Szabo G (2007) Viral and host factors induce macrophage activation and loss of toll-like receptor tolerance in chronic HCV infection. Gastroenterolgy 133:1627–1636CrossRefGoogle Scholar
  48. 49.
    Uesgi T, Froh M, Arteel GE, Bradford BU, Thurman RG (2001) Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34:101–108CrossRefGoogle Scholar
  49. 50.
    Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG (2001) Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol 166:4737–4742PubMedGoogle Scholar
  50. 51.
    Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G (2008) The critical role of Toll-like receptor 4 in alcoholic liver disease is independent of the common TLR adaptor, MyD88. Hepatology 48:1224–1231CrossRefPubMedGoogle Scholar
  51. 52.
    Gustot T, Lemmers A, Moreno C, Nagy N, Quertinmont E, Nicaise C, Franchimont D et al (2006) Differential liver sensitization to toll-like receptor pathways in mice with alcoholic fatty liver. Hepatology 43:989–1000CrossRefPubMedGoogle Scholar
  52. 53.
    Rivera CA, Adegboyega P, van Rooijen N, Tagalicud A, Allman M, Wallace M (2007) Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol 47:571–579CrossRefPubMedGoogle Scholar
  53. 54.
    Szabo G, Velayudham A, Romics L Jr, Mandrekar P (2005) Modulation of non-alcoholic steatohepatitis by pattern ­recognition receptors in mice: the role of Toll-like receptors 2 and 4. Alcohol Clin Exp Res 29:140s–145sCrossRefPubMedGoogle Scholar
  54. 55.
    Zhang X, Yu WP, Gao L, Wei KB, Ju JL, Xu JZ (2004) Effects of lipopolysaccharides stimulated Kupffer cells on activation of rat hepatic stellate cells. World J Gastroenterol 10:610613Google Scholar
  55. 56.
    Kisseleva T, Brenner DA (2007) Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J Gastroenterol Hepatol 22:S73–S78CrossRefGoogle Scholar
  56. 57.
    Wang AP, Migita K, Ito M, Takii Y, Daikoku M, Yokoyama T, Komori A, Nakamura M, Yatsuhashi H, Ishibashi H (2005) Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. J Autoimmun 25:85–91CrossRefPubMedGoogle Scholar
  57. 58.
    Kikuchi K, Lian ZX, Yang GX, Ansari AA, Ikehara S, Kaplan M, Miyakawa H, Coppel RL, Gershwin ME (2005) Bacterial CpG induces hyper-IgM production in CD27(+) memory B-treated cells in primary biliary cirrhosis. Gastroenterology 128:304–312CrossRefPubMedGoogle Scholar
  58. 59.
    Seki E, Tsutsui H, Iimuro Y, Naka T, Son G, Akira S, Kishimoto T et al (2005) Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration. Hepatology 41:443–450CrossRefPubMedGoogle Scholar
  59. 60.
    Campbell JS, Riehle KJ, Brooling JT, Bauer RL, Mitchell C, Fausto N (2006) Proinflammatory cytokine production in liver regeneration is MyD88-dependent, but independent of CD14, TLR2, and TLR4. J Immunol 176:2522–2528PubMedGoogle Scholar
  60. 61.
    Sun R, Gao B (2004) Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma). Gastroenterology 127:1525–1539CrossRefPubMedGoogle Scholar
  61. 62.
    Velayudham A, Dolganiuc A, Kurt-Jones E, Szabo G (2006) Critical role for Toll-like receptors and the common adaptor, MyD88, in granulomas and sensitization to injury. J Hepatology 45:813–824CrossRefGoogle Scholar
  62. 63.
    Zhai Y, Shen XD, O’Connell R, Gao F, Lassman C, Busuttil RW, Cheng G et al (2004) Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway. J Immunol 173:7115–7119PubMedGoogle Scholar
  63. 64.
    Tsoulfas G, Takahashi Y, Ganster RW, Yagnik G, Guo Z, Fung JJ, Murase N et al (2002) Activation of the lipopolysaccharide signaling pathway in hepatic transplantation preservation injury. Transplantation 74:7–13CrossRefPubMedGoogle Scholar
  64. 65.
    Visintin A, Halmen KA, Latz E, Monks BG, Golenbock DT (2005) Pharmacological inhibition of endotoxin responses is achieved by targeting the TLR4 co-receptor, MD-2. J Immunol 175:6465–6472PubMedGoogle Scholar
  65. 66.
    Kawata T, Bristol JR, Rossignol DP, Rose JR, Kobayashi S, Yokohama H, Ishibashi A et al (1999) E5531, a synthetic non-toxic lipid A derivative blocks the immunobiological activities of lipopolysaccharide. Br J Pharmacol 127: 853–862CrossRefPubMedGoogle Scholar
  66. 67.
    Bartfai T, Behrens MM, Gaidarova S, Pemberton J, Shivanyuk A, Rebek J Jr (2003) A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses. Proc Natl Acad Sci U S A 100:7971–7976CrossRefPubMedGoogle Scholar
  67. 68.
    Xie FY, Woodle MC, Lu PY (2006) Harnessing in vivo siRNA delivery for drug discovery and therapeutic development. Drug Discov Today 11:67–73CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations