Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Negative regulation of Toll-like receptor-mediated immune responses

Key Points

  • The strength and pervasive nature of Toll-like receptor (TLR) signalling necessitates a powerful and comprehensive negative regulatory mechanism to prevent autoimmune damage. This review discusses our current understanding of the negative regulators of TLR responses.

  • There are at least five layers of negative regulation of TLR signalling. These range from extracellular decoy receptors to intracellular inhibitors, membrane-bound suppressors, degradation of TLRs, and TLR-induced apoptosis.

  • Soluble decoy TLRs are potentially powerful competitors for TLR agonists, reminiscent of soluble chemokines and cytokine receptors. So far, only soluble TLR4 and TLR2 have been identified, and their role might be as an important first-line negative regulatory mechanism.

  • Intracellular negative regulators so far identified include MyD88s, IRAKM, SOCS1, NOD2, phosphatidylinositol 3-kinase, TOLLIP and A20. This group is perhaps the best studied of all the regulators. They function at various stages of the TLR signalling cascade but concentrate principally on the MyD88-dependent pathway.

  • Transmembrane protein regulators include ST2, SIGIRR, TRAILR and RP105. These proteins inhibit TLR functions either by sequestration of adaptor proteins (ST2) and transcription factors (TRAILR), or by interfering with the binding of TLR agonists to their respective TLRs (SIGIRR and RP105).

  • Reduction of TLR expression could be by ubiquitylation (TRIAD3A), promoting proteolytic degradation of TLRs, or through inhibition of the transcription or stability of TLR-encoding mRNAs (interleukin-10, transforming-growth factor-β and lipopolysaccharide).

  • The last line of negative regulation is self-destruction. Excessive TLR activation could lead to caspase-dependent (through the death domain of MyD88) and caspase-independent apoptosis.

  • The existence of multiple and apparently non-redundant negative regulators of TLRs indicate that either the regulators function in a cascade manner or that each regulator is necessary but insufficient to control a particular TLR signalling pathway. The genetic polymorphism of the regulators and what regulates the negative regulator remains to be determined. The biological functions of some of the negative regulators in vivo also remain to be determined.

Abstract

Toll-like receptors (TLRs) are involved in host defence against invading pathogens, functioning as primary sensors of microbial products and activating signalling pathways that induce the expression of immune and pro-inflammatory genes. However, TLRs have also been implicated in several immune-mediated and inflammatory diseases. As the immune system needs to constantly strike a balance between activation and inhibition to avoid detrimental and inappropriate inflammatory responses, TLR signalling must be tightly regulated. Here, we discuss the various negative regulatory mechanisms that have evolved to attenuate TLR signalling to maintain this immunological balance.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Toll-like receptors recognize a range of pathogen-derived products.
Figure 2: Adaptor molecules for Toll-like receptor signalling.
Figure 3: Soluble Toll-like receptor regulators.
Figure 4: Intracellular Toll-like receptor regulators.
Figure 5: Transmembrane Toll-like receptor regulators.
Figure 6: Toll-like receptors induce apoptotic and anti-apoptotic pathways.

Similar content being viewed by others

References

  1. Hornung, V. et al. Quantitative expression of Toll-like receptor 1–10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J. Immunol. 168, 4531– 4537 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Muzio, M. et al. Differential expression and regulation of Toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J. Immunol. 164, 5998– 6004 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Rock, F. L., Hardiman, G., Timans, J. C., Kastelein, R. A. & Bazan, J. F. A family of human receptors structurally related to Drosophila Toll. Proc. Natl Acad. Sci. USA 95, 588– 593 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394– 397 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Hoebe, K. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743– 748 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Lund, J., Sato, A., Akira, S., Medzhitov, R. & Iwasaki, A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J. Exp. Med. 198, 513– 520 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526– 1529 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Diebold, S. S., Kaisho, T., Hemmi, H., Akira, S. & Reis e Sousa, C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303, 1529– 1531 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Hornung, V. et al. Replication-dependent potent IFN-α induction in human plasmacytoid dendritic cells by a single-stranded RNA virus. J. Immunol. 173, 5935– 5943 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Poltorak, A. et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085– 2088 (1998). This is the first evidence that TLR4 is required for LPS signals.

    Article  CAS  PubMed  Google Scholar 

  11. Underhill, D. M. et al. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401, 811– 815 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099– 1103 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, D. et al. A Toll-like receptor that prevents infection by uropathogenic bacteria. Science 303, 1522– 1526 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Meier, A. et al. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell. Microbiol. 5, 561– 570 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Campos, M. A. et al. Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J. Immunol. 167, 416– 423 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Bowie, A. & O'Neill, L. A. The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products. J. Leukoc. Biol. 67, 508– 514 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Slack, J. L. et al. Identification of two major sites in the type I interleukin-1 receptor cytoplasmic region responsible for coupling to pro-inflammatory signaling pathways. J. Biol. Chem. 275, 4670– 4678 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Beutler, B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430, 257– 263 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675– 680 (2001).

    Article  CAS  Google Scholar 

  20. Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135– 145 (2001).

    Article  CAS  Google Scholar 

  21. Cook, D. N., Pisetsky, D. S. & Schwartz, D. A. Toll-like receptors in the pathogenesis of human disease. Nature Immunol. 5, 975– 979 (2004).

    Article  CAS  Google Scholar 

  22. Eriksson, U. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nature Med. 9, 1484– 1490 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Michelsen, K. S. et al. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc. Natl Acad. Sci. USA 101, 10679– 10684 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bjorkbacka, H. et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Med. 10, 416– 421 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Kiechl, S. et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. 347, 185– 192 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Kolek, M. J. et al. Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes. Am. Heart J. 148, 1034– 1040 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Zipris, D. et al. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J. Immunol. 174, 131– 142 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Kerfoot, S. M. et al. TLR4 contributes to disease-inducing mechanisms resulting in central nervous system autoimmune disease. J. Immunol. 173, 7070– 7077 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603– 607 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Eisenbarth, S. C. et al. Lipopolysaccharide-enhanced, Toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J. Exp. Med. 196, 1645– 1651 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dabbagh, K., Dahl, M. E., Stepick-Biek, P. & Lewis, D. B. Toll-like receptor 4 is required for optimal development of TH2 immune responses: role of dendritic cells. J. Immunol. 168, 4524– 4530 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Iwahashi, M. et al. Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum. 50, 1457– 1467 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Pierer, M. et al. Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J. Immunol. 172, 1256– 1265 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Wedzicha, J. A. Exacerbations: etiology and pathophysiologic mechanisms. Chest 121, 136S– 141S (2002).

    Google Scholar 

  35. Adachi, K. et al. Plasmodium berghei infection in mice induces liver injury by an IL-12- and Toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J. Immunol. 167, 5928– 5934 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Coban, C. et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. 201, 19– 25 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang, T. et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nature Med. 10, 1366– 1373 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Netea, M. G. et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol. 172, 3712– 3718 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499– 511 (2004).

    Article  CAS  Google Scholar 

  40. Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T. & Seya, T. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-β induction. Nature Immunol. 4, 161– 167 (2003).

    Article  CAS  Google Scholar 

  41. Yamamoto, M. et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-β promoter in the Toll-like receptor signaling. J. Immunol. 169, 6668– 6672 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Yamamoto, M. et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nature Immunol. 4, 1144– 1150 (2003).

    Article  CAS  Google Scholar 

  43. Fitzgerald, K. A. et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413, 78– 83 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Yamamoto, M. et al. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420, 324– 329 (2002). References 40 to 44 reported the identification and functions of adaptor molecules in the TLR signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  45. Kawai, T. et al. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J. Immunol. 167, 5887– 5894 (2001). This is the first evidence of the presence of a MyD88-independent TLR signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  46. Toshchakov, V. et al. TLR4, but not TLR2, mediates IFN-β-induced STAT1α/β-dependent gene expression in macrophages. Nature Immunol. 3, 392– 398 (2002).

    Article  CAS  Google Scholar 

  47. Dumitru, C. D. et al. TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103, 1071– 1083 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Huang, Q. et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nature Immunol. 5, 98– 103 (2004).

    Article  CAS  Google Scholar 

  49. Colotta, F., Dower, S. K., Sims, J. E. & Mantovani, A. The type II 'decoy' receptor: a novel regulatory pathway for interleukin 1. Immunol. Today 15, 562– 526 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Qureshi, S. T. et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189, 615– 625 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Iwami, K. I. et al. Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J. Immunol. 165, 6682– 6686 (2000). This is the first report of the presence and function of soluble TLR.

    Article  CAS  PubMed  Google Scholar 

  52. LeBouder, E. et al. Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J. Immunol. 171, 6680– 6689 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Iwaki, D. et al. The extracellular Toll-like receptor 2 domain directly binds peptidoglycan derived from Staphylococcus aureus. J. Biol. Chem. 277, 24315– 24320 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Hardiman, G. et al. Genetic structure and chromosomal mapping of MyD88. Genomics 45, 332– 339 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Janssens, S., Burns, K., Tschopp, J. & Beyaert, R. Regulation of interleukin-1- and lipopolysaccharide-induced NF-κB activation by alternative splicing of MyD88. Curr. Biol. 12, 467– 471 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Burns, K. et al. Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J. Exp. Med. 197, 263– 268 (2003). References 55 and 56 are key papers identifying MyD88s as an inhibitor of TLR signalling.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Janssens, S., Burns, K., Vercammen, E., Tschopp, J. & Beyaert, R. MyD88S, a splice variant of MyD88, differentially modulates NF-κB- and AP-1-dependent gene expression. FEBS Lett. 548, 103– 107 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Janssens, S. & Beyaert, R. Functional diversity and regulation of different interleukin-1 receptor-associated kinase (IRAK) family members. Mol. Cell 11, 293– 302 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Wesche, H. et al. IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family. J. Biol. Chem. 274, 19403– 19410 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Kobayashi, K. et al. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110, 191– 202 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Hardy, M. P. & O'Neill, L. A. The murine IRAK2 gene encodes four alternatively spliced isoforms, two of which are inhibitory. J. Biol. Chem. 279, 27699– 27708 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Alexander, W. S. Suppressors of cytokine signalling (SOCS) in the immune system. Nature Rev. Immunol. 2, 410– 416 (2002).

    Article  CAS  Google Scholar 

  63. Naka, T. et al. Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. Proc. Natl Acad. Sci. USA 95, 15577– 15582 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Starr, R. et al. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc. Natl Acad. Sci. USA 95, 14395– 14399 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kinjyo, I. et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583– 591 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Nakagawa, R. et al. SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677– 687 (2002). References 65 and 66 are key papers identifying SOCS1 as an inhibitor of TLR signalling.

    Article  CAS  PubMed  Google Scholar 

  67. Baetz, A., Frey, M., Heeg, K. & Dalpke, A. H. Suppressor of cytokine signaling (SOCS) proteins indirectly regulate Toll-like receptor signaling in innate immune cells. J. Biol. Chem. 279, 54708– 54715 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Gingras, S., Parganas, E., de Pauw, A., Ihle, J. N. & Murray, P. J. Re-examination of the role of suppressor of cytokine signaling 1 (SOCS1) in the regulation of Toll-like receptor signaling. J. Biol. Chem. 279, 54702– 54707 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Inohara, N. & Nunez, G. NODs: intracellular proteins involved in inflammation and apoptosis. Nature Rev. Immunol. 3, 371– 382 (2003).

    Article  CAS  Google Scholar 

  70. Harton, J. A., Linhoff, M. W., Zhang, J. & Ting, J. P. Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J. Immunol. 169, 4088– 4093 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Inohara, N. et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. 278, 5509– 5512 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Girardin, S. E. et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. 278, 8869– 8872 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Watanabe, T., Kitani, A., Murray, P. J. & Strober, W. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nature Immunol. 5, 800– 808 (2004).

    Article  CAS  Google Scholar 

  74. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603– 606 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599– 603 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Netea, M. G. et al. NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease. Eur. J. Immunol. 34, 2052– 2059 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Maeda, S. et al. Nod2 mutation in Crohn's disease potentiates NF-κB activity and IL-1β processing. Science 307, 734– 738 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731– 734 (2005). References 77 and 78 provided evidence that NOD2 might not be a negative regulator of TLR signalling.

    Article  CAS  PubMed  Google Scholar 

  79. Katso, R. et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell. Dev. Biol. 17, 615– 675 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Fukao, T. et al. PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nature Immunol. 3, 875– 881 (2002).

    Article  CAS  Google Scholar 

  81. Burns, K. et al. Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nature Cell Biol. 2, 346– 351 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Bulut, Y., Faure, E., Thomas, L., Equils, O. & Arditi, M. 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 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Zhang, G. & Ghosh, S. Negative regulation of Toll-like receptor-mediated signaling by Tollip. J. Biol. Chem. 277, 7059– 7065 (2002). TOLLIP is the first identified intracellular TLR regulator. References 81–83 demonstrate that TOLLIP suppresses MyD88-dependent signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  84. Melmed, G. et al. Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J. Immunol. 170, 1406– 1415 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Li, T., Hu, J. & Li, L. Characterization of Tollip protein upon lipopolysaccharide challenge. Mol. Immunol. 41, 85– 92 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Nalefski, E. A. & Falke, J. J. The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci. 5, 2375– 2390 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Opipari, A. W. Jr., Boguski, M. S. & Dixit, V. M. The A20 cDNA induced by tumor necrosis factor α encodes a novel type of zinc finger protein. J. Biol. Chem. 265, 14705– 14708 (1990).

    CAS  PubMed  Google Scholar 

  88. Krikos, A., Laherty, C. D. & Dixit, V. M. Transcriptional activation of the tumor necrosis factor α-inducible zinc finger protein, A20, is mediated by κB elements. J. Biol. Chem. 267, 17971– 17976 (1992).

    CAS  PubMed  Google Scholar 

  89. Boone, D. L. et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nature Immunol. 5, 1052– 1060 (2004).

    Article  CAS  Google Scholar 

  90. Klemenz, R., Hoffmann, S. & Werenskiold, A. K. Serum- and oncoprotein-mediated induction of a gene with sequence similarity to the gene encoding carcinoembryonic antigen. Proc. Natl Acad. Sci. USA 86, 5708– 5712 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tominaga, S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 258, 301– 304 (1989).

    Article  CAS  PubMed  Google Scholar 

  92. Bergers, G., Reikerstorfer, A., Braselmann, S., Graninger, P. & Busslinger, M. Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J. 13, 1176– 1188 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Xu, D. et al. Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J. Exp. Med. 187, 787– 794 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lohning, M. et al. T1/ST2 is preferentially expressed on murine TH2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for TH2 effector function. Proc. Natl Acad. Sci. USA 95, 6930– 6935 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Coyle, A. J. et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J. Exp. Med. 190, 895– 902 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hoshino, K. et al. The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function. J. Exp. Med. 190, 1541– 1548 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Senn, K. A. et al. T1-deficient and T1-Fc-transgenic mice develop a normal protective TH2-type immune response following infection with Nippostrongylus brasiliensis. Eur. J. Immunol. 30, 1929– 1938 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Townsend, M. J., Fallon, P. G., Matthews, D. J., Jolin, H. E. & McKenzie, A. N. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069– 1076 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Brint, E. K. et al. Characterization of signaling pathways activated by the interleukin 1 (IL-1) receptor homologue T1/ST2. A role for Jun N-terminal kinase in IL-4 induction. J. Biol. Chem. 277, 49205– 49211 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Brint, E. K. et al. ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nature Immunol. 5, 373– 379 (2004). This paper shows that TLR signalling could be inhibited by other members of the TIR superfamily by sequestrating MyD88 and MAL function. Also see SIGIRR in reference 110 and 111.

    Article  CAS  Google Scholar 

  101. Saccani, S., Polentarutti, N., Penton-Rol, G., Sims, J. E. & Mantovani, A. Divergent effects of LPS on expression of IL-1 receptor family members in mononuclear phagocytes in vitro and in vivo. Cytokine 10, 773– 780 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Kumar, S., Tzimas, M. N., Griswold, D. E. & Young, P. R. Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem. Biophys. Res. Commun. 235, 474– 478 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Kuroiwa, K., Arai, T., Okazaki, H., Minota, S. & Tominaga, S. Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem. Biophys. Res. Commun. 284, 1104– 1108 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Oshikawa, K. et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am. J. Respir. Crit. Care Med. 164, 277– 281 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Tajima, S., Oshikawa, K., Tominaga, S. & Sugiyama, Y. The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Chest 124, 1206– 1214 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Weinberg, E. O. et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106, 2961– 2966 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sweet, M. J. et al. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J. Immunol. 166, 6633– 6639 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Leung, B. P., Xu, D., Culshaw, S., McInnes, I. B. & Liew, F. Y. A novel therapy of murine collagen-induced arthritis with soluble T1/ST2. J. Immunol. 173, 145– 150 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Thomassen, E., Renshaw, B. R. & Sims, J. E. Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 11, 389– 399 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Wald, D. et al. SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature Immunol. 4, 920– 927 (2003).

    Article  CAS  Google Scholar 

  111. Garlanda, C. et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Natl Acad. Sci. USA 101, 3522– 3526 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Polentarutti, N. et al. Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR. Eur. Cytokine Netw. 14, 211– 218 (2003).

    CAS  PubMed  Google Scholar 

  113. Wu, G. S., Burns, T. F., Zhan, Y., Alnemri, E. S. & El-Deiry, W. S. Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res. 59, 2770– 2775 (1999).

    CAS  PubMed  Google Scholar 

  114. Diehl, G. E. et al. TRAIL-R as a negative regulator of innate immune cell responses. Immunity 21, 877– 889 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503– 533 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Chuang, T. H. & Ulevitch, R. J. Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nature Immunol. 5, 495– 502 (2004).

    Article  CAS  Google Scholar 

  117. McCartney-Francis, N., Jin, W. & Wahl, S. M. Aberrant Toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-β1 signaling pathway. J. Immunol. 172, 3814– 3821 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Naiki, Y. et al. Transforming growth factor-β differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling J. Biol. Chem. 280, 5491– 5495 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Re, F. & Strominger, J. L. IL-10 released by concomitant TLR2 stimulation blocks the induction of a subset of TH1 cytokines that are specifically induced by TLR4 or TLR3 in human dendritic cells. J. Immunol. 173, 7548– 7555 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Rehli, M. Of mice and men: species variations of Toll-like receptor expression. Trends Immunol. 23, 375– 378 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Abreu, M. T. et al. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J. Immunol. 167, 1609– 1616 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. Aliprantis, A. O. et al. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 285, 736– 739 (1999). This is the first evidence that TLR is also a death receptor.

    Article  CAS  PubMed  Google Scholar 

  123. Aliprantis, A. O., Yang, R. B., Weiss, D. S., Godowski, P. & Zychlinsky, A. The apoptotic signaling pathway activated by Toll-like receptor-2. EMBO J. 19, 3325– 3336 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bannerman, D. D., Erwert, R. D., Winn, R. K. & Harlan, J. M. TIRAP mediates endotoxin-induced NF-κB activation and apoptosis in endothelial cells. Biochem. Biophys. Res. Commun. 295, 157– 162 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Choi, K. B. et al. Lipopolysaccharide mediates endothelial apoptosis by a FADD-dependent pathway. J. Biol. Chem. 273, 20185– 20188 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Ruckdeschel, K., Mannel, O. & Schrottner, P. Divergence of apoptosis-inducing and preventing signals in bacteria-faced macrophages through myeloid differentiation factor 88 and IL-1 receptor-associated kinase members. J. Immunol. 168, 4601– 4611 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Hsu, L. -C. et al. The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4. Nature 428, 341– 345 (2004). This report shows that TLR induces apoptosis by the MyD88-independent TLR signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  128. Kim, S. O., Ono, K., Tobias, P. S. & Han, J. Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death. J. Exp. Med. 197, 1441– 1452 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Divanovic, S. et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunol. 24 Apr 2005 (10.1038/ni1198).

Download references

Acknowledgements

We thank The Wellcome Trust, The Medical Research Council, UK, The Science Foundation Ireland and the European Commission for financial support.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Foo Y. Liew or Damo Xu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

A20

CD14

IRAK1

IRAK4

MAL

MD2

MyD88

NOD2

SIGIRR

SOCS1

ST2

TLR1

TLR2

TLR3

TLR4

TLR9

TOLLIP

TRAF6

TRAIL

TRAILR

TRAM

TRIF

FURTHER INFORMATION

Foo Y. Liew's homepage

Dano Xu's homepage

Glossary

PATHOGEN-ASSOCIATED MOLECULAR PATTERN

A molecular pattern that is found in pathogens but not mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind TLRs.

ORPHAN RECEPTOR

A receptor without a known ligand.

TIR DOMAIN

An amino-acid sequence of the cytoplasmic region that is highly conserved among TLRs and IL-1 receptor superfamily.

CpG DNA

DNA oligodeoxynucleotide sequences that include a cytosine–guanosine sequence and certain flanking nucleotides, which have been found to induce innate immune responses through interaction with TLR9.

LPS TOLERANCE

A transient state of hypo-responsiveness to subsequent stimulation with lipopolysaccharide (LPS), which is induced by the administration of TLR ligands in vivo and in vitro.

ENDOTOXIN SHOCK

A clinical condition that is induced by hyper-reactivity of the innate immune system to bacterial LPS. It is mediated by the pro-inflammatory cytokines interleukin-1 (IL-1) and tumour-necrosis factor (TNF), which are produced in high amounts owing to sustained stimulation of TLR4 by LPS.

CROHN'S DISEASE

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is believed to result from an abnormal T-cell-mediated immune response to commensal bacteria.

IL-1 RECEPTOR ACCESSORY PROTEIN

A protein that forms a heterodimer with the type I IL-1 receptor. IL-1 receptor accessory protein does not bind IL-1 directly on its own but is essential for downstream IL-1 receptor complex signalling.

UBIQUITYLATION

The attachment of the small protein ubiquitin to lysine residues present in other proteins. This tags these proteins for rapid cellular degradation.

BRADYCARDIA

Slow rate of heart beat contraction, resulting in slow pulse rate. In febrile states, for each degree rise in body temperature, the expected increase in pulse rate is 10 beats per minute. When the latter does not occur, the term 'relative bradycardia' is used.

SMALL INTERFERING RNA

Short (21-base pairs) double-stranded RNA fragments that can direct RNA-degradative machinery to homologous endogenous RNA sequences when introduced into cells, thereby inhibiting the expression of the targeted genes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liew, F., Xu, D., Brint, E. et al. Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol 5, 446–458 (2005). https://doi.org/10.1038/nri1630

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1630

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing