The role of Toll-like receptors in immune disorders

Expert Opinion on Biological Therapy

Volumn 6, Issue 3, 2006, Pages 203-214

  Uematsu, Satoshi ^a   Akira, Shizuo ^a,b  

^a OSAKA UNIVERSITY   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

Autoimmune disease; Polymorphism; Toll like receptor

Indexed keywords

ASPARTIC ACID; BETA INTERFERON; CASPASE RECRUITMENT DOMAIN PROTEIN 15; INTERFERON; INTERLEUKIN 1 RECEPTOR ASSOCIATED KINASE 1; MYELOID DIFFERENTIATION FACTOR 88; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 1; TOLL LIKE RECEPTOR 11; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 5; TOLL LIKE RECEPTOR 6; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8; TOLL LIKE RECEPTOR 9; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; AUTOIMMUNE DISEASE; DENDRITIC CELL; GENE TARGETING; GENETIC POLYMORPHISM; IMMUNOCOMPETENT CELL; IMMUNOPATHOLOGY; INFLAMMATORY CELL; INNATE IMMUNITY; PATHOGENESIS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM;

ANIMALS; HUMANS; IMMUNE SYSTEM DISEASES; IMMUNITY, NATURAL; INTERLEUKINS; POLYMORPHISM, GENETIC; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS;

EID: 33644775552     PISSN: 14712598     EISSN: None     Source Type: Journal    
DOI: 10.1517/14712598.6.3.203     Document Type: Review

References (140)

1. JANEWAY CA JR, MEDZHITOV R: Innate immune recognition. Annu. Rev. Immunol. (2002) 20:197-216.
2. AKIRA S, TAKEDA K: Toll-like receptor signalling. Nat. Rev. Immunol. (2004) 4:499-511.
3. TAKEDA K, AKIRA S: Toll-like receptors in innate immunity. Int. Immunol. (2005) 17:1-14.
4. POLTORAK A, HE X, SMIRNOVA I et al.: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science (1998) 282:2085-2088.
5. HOSHINO K, TAKEUCHI O, KAWAI T et al.: Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. (1999) 162:3749-3752.
6. TAKEUCHI O, HOSHINO K, KAWAI T et al.: Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity (1999) 11:443-451.
7. AKIRA S: Toll receptor families: structure and function. Semin. Immunol. (2004) 16:1-2.
8. ALEXOPOULOU L, THOMAS V, SCHNARE M et al.: Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat. Med. (2002) 8:878-884.
9. SCHRODER NW, OPITZ B, LAMPING N et al.: Involvement of lipopoiysaccharide binding protein, CD14, and Toll-like receptors in the initiation of innate immune responses by Treponema glycolipids. J. Immunol. (2000) 165:2683-2693.
10. OPITZ B, SCHRODER NW, SPREITZER I et al.: Toll-like receptor-2 mediates Treponema glycolipid and lipoteichoic acid-induced NF-kappaB translocation. J. Biol. Chem. (2001) 276:22041-22047.
11. TRAVASSOS LH, GIRARDIN SE, PHILPOTT DJ et al.: Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep. (2004) 5:1000-1006.
12. BROWN GD, GORDON S: Immune recognition. A new receptor for beta-glucans. Nature (2001) 413:36-37.
13. HOEBE K, GEORGEL P, RUTSCHMANN S et al.: CD36 is a sensor of diacylglycerides. Nature (2005) 433:523-527.
14. ALEXOPOULOU L, HOLT AC, MEDZHITOV R, FLAVELL RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature (2001) 413:732-738.
15. HAYASHI F, SMITH KD, OZINSKY A et al.: The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature (2001) 410:1099-1103.
16. ZHANG D, ZHANG G, HAYDEN MS et al.: A toll-like receptor that prevents infection by uropathogenic bacteria. Science (2004) 303:1522-1526.
17. YAROVINSKY F, ZHANG D, ANDERSEN JF et al.: TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science (2005) 308:1626-1629.
18. HEMMI H, KAISHO T, TAKEUCHI O et al.: Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. (2002) 3:196-200.
19. ITO T, AMAKAWA R, KAISHO T et al.: Interferon-alpha and interleukin-12 are induced differentially by Toll-like receptor 7 ligands in human blood dendritic cell subsets. J. Exp. Med. (2002) 195:1507-1512.
20. DIEBOLD SS, KAISHO T, HEMMI H, AKIRA S, REIS E, SOUSA C: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science (2004) 303:1529-1531.
21. HEMMI H, TAKEUCHI O, KAWAI T et al.: A Toll-like receptor recognizes bacterial DNA. Nature (2000) 408:740-745.
22. 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. (2003) 198:513-520.
23. COBAN C, ISHII KJ, KAWAI T et al.: Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J. Exp. Med. (2005) 201:19-25.
24. SEYA T, OSHIUMI H, SASAI M, AKAZAWA T, MATSUMOTO M: TICAM-1 and TICAM-2: toll-like receptor adapters that participate in induction of Type 1 interferons. Int. J. Biochem. Cell Biol. (2005) 37:524-529.
25. SANJO H, TAKEDA K, TSUJIMURA T, NINOMIYA-TSUJI J, MATSUMOTO K, AKIRA S: TAB2 is essential for prevention of apoptosis in fetal liver but not for interleukin-1 signaling. Mol. Cell. Biol. (2003) 23:1231-1238.
26. SATO S, SANJO H, TAKEDA K et al.: Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat. Immunol. (2005) 6:1087-1095.
27. AKIRA S: Toll-like receptor signaling. J. Biol. Chem. (2003) 278:38105-38108.
28. FITZGERALD KA, PALSSON-MCDERMOTT EM, BOWIE AG et al.: Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature (2001) 413:78-83.
29. YAMAMOTO M, SATO S, HEMMI H et al.: Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature (2002) 420:324-329.
30. HORNG T, BARTON GM, FLAVELL RA, MEDZHITOV R: The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature (2002) 420:329-333.
31. COOK DN, PISETSKY DS, SCHWARTZ DA: Toll-like receptors in the pathogenesis of human disease. Nat. Immunol. (2004) 5:975-979.
32. SCHRODER NW, SCHUMANN RR: Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect. Dis. (2005) 5:156-164.
33. ARBOUR NC, LORENZ E, SCHUTTE BC et al.: TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat. Genet. (2000) 25:187-191.
34. LORENZ E, MIRA JP, FREES KL, SCHWARTZ DA: Relevance of mutations in the TLR4 receptor in patients with Gram-negative septic shock. Arch. Intern. Med. (2002) 162:1028-1032.
35. TAL G, MANDELBERG A, DALAL I et al.: Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J. Infect. Dis. (2004) 189:2057-2063.
36. READ RC, PULLIN J, GREGORY S et al.: A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J. Infect. Dis. (2001) 184:640-642.
37. KIECHL S, LORENZ E, REINDL M et al.: Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med. (2002) 347:185-192.
38. AMEZIANE N, BEILLAT T, VERPILLAT P et al.: Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler. Thromb. Vasc. Biol (2003) 23:e61-e64.
39. BOEKHOLDT SM, AGEMA WR, PETERS RJ et al.: Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation (2003) 107:2416-2421.
40. MICHELSEN KS, DOHERTY TM, SHAH PK, ARDITI M: Role of Toll-like receptors in atherosclerosis. Circ. Res. (2004) 95:e96-e97.
41. LORENZ E, SCHWARTZ DA, MARTIN PJ et al.: Association of TLR4 mutations and the risk for acute GVHD after HLA-matched-sibling hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. (2001) 7:384-387.
42. TOROK HP, GLAS J, TONENCHI L, BRUENNLER G, FOLWACZNY M, FOLWACZNY C: Crohn's disease is associated with a toll-like receptor-9 polymorphism. Gastroenterology (2004) 127:365-366.
43. YANG IA, BARTON SJ, RORKE S et al.: Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun. (2004) 5:41-45.
44. RADSTAKE TR, FRANKE B, HANSSEN S et al.: The Toll-like receptor 4 Asp299Gly functional variant is associated with decreased rheumatoid arthritis disease susceptibility but does not influence disease severity and/or outcome. Arthritis Rheum. (2004) 50:999-1001.
45. RUDOFSKY G JR, REISMANN P, WITTE S et al.: Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with Type 2 diabetes. Diabetes Care (2004) 27:179-183.
46. PALMER SM, BURCH LH, DAVIS RD et al.: The role of innate immunity in acute alfograft rejection after lung transplantation. Am. J. Respir. Crit. Care Med. (2003) 168:628-632.
47. MINORETTI P, GAZZARUSO C, VITO CD et al.: Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease. Neurosci. Lett. (2006) 391:147-149.
48. SCHRODER NW, MEISTER D, WOLFF V et al.: Chronic periodontal disease is associated with single-nucleotide polymorphisms of the human TLR-4 gene. Genes Immun. (2005) 6:448-451.
49. ROHDE G, KLEIN W, ARINIR U et al.: Association of the ASP299GLYTLR4 polymorphism with COPD. Respir. Med. (2006) (In Press).
50. LORENZ E, MIRA JP, CORNISH KL, ARBOUR NC, SCHWARTZ DA: A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect. Immun. (2000) 68:6398-6401.
51. OGUS AC, YOLDAS B, OZDEMIR T et al.: The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur. Respir. J. (2004) 23:219-223.
52. MOORE CE, SEGAL S, BERENDT AR, HILL AV, DAY NP: Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin. Diagn. Lab. Immunol. (2004) 11:1194-1197.
53. AHMAD-NEJAD P, MRABET-DAHBI S, BREUER K et al.: The toll-like receptor 2 R753Q polymorphism defines a subgroup of patients with atopic dermatitis having severe phenotype. J. Allergy Clin. Immunol. (2004) 113:565-567.
54. MULLICK AE, TOBIAS PS, CURTISS LK: Modulation of atherosclerosis in mice by Toll-like receptor 2. J. Clin. Invest. (2005) 115:3149-3156.
55. HAMANN L, GOMMA A, SCHRODER NW et al.: A frequent toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis. J. Mol. Med. (2005) 83:478-485.
56. ROSENKRANZ ME, SCHULTE DJ, AGLE LM et al.: TLR2 and MyD88 contribute to Lactobacillus casei extract-induced focal coronary arteritis in a mouse model of Kawasaki disease. Circulation (2005) 112:2966-2973.
57. SCHRODER NW, DITERICH I, ZINKE A et al.: Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease. J. Immunol. (2005) 175:2534-2540.
58. KANG TJ, CHAE GT: Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol. Med. Microbiol. (2001) 31:53-58.
59. KANG TJ, LEE SB, CHAE GT: A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine (2002) 20:56-62.
60. KRUTZIK SR, OCHOA MT, SIELING PA et al.: Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat. Med. (2003) 9:525-532.
61. BOCHUD PY, HAWN TR, ADEREM A: Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J. Immunol. (2003) 170:3451-3454.
62. MALHOTRA D, RELHAN V, REDDY BS, BAMEZAI R: TLR2 Arg677Trp polymorphism in leprosy: revisited. Hum. Genet. (2005) 116:413-415.
63. SMIRNOVA I, MANN N, DOLS A et al.: Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc. Natl. Acad. Sci. USA (2003) 100:6075-6080.
64. BEN-ALI M, BARBOUCHE MR, BOUSNINA S, CHABBOU A, DELLAGI K: Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin. Diagn. Lab. Immunol. (2004) 11:625-626.
65. HAWN TR, VERBON A, LETTINGA KD et al.: A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J. Exp. Med. (2003) 198:1563-1572.
66. DUNSTAN SJ, HAWN TR, HUE NT et al.: Host susceptibility and clinical outcomes in toll-like receptor 5-deficient patients with typhoid fever in Vietnam. J. Infect. Dis. (2005) 191:1068-1071.
67. LAZARUS R, KLIMECKI WT, RABY BA et al.: Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three US ethnic groups and exploratory case-control disease association studies. Genomics (2003) 81:85-91.
68. TANTISIRA K, KLIMECKI WT, LAZARUS R et al.: Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun. (2004) 5:343-346.
69. HOFFJAN S, STEMMLER S, PARWEZ Q et al.: Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Med Genet. (2005) 6:34.
70. LAZARUS R, RABY BA, LANGE C et al.: TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples. Am. J. Respir. Crit. Care Med. (2004) 170:594-600.
71. MARTINON F, TSCHOPP J: NLRs join TLRs as innate sensors of pathogens. Trends Immunol. (2005) 26:447-454.
72. GIRARDIN SE, BONEGA IG, CARNEIRO LA et al.: Nod1 detects a unique muropeptide from Gram-negative bacterial peptidogiycan. Science (2003) 300:1584-1587.
73. CHAMAILLARD M, HASHIMOTO M, HORIE Y et al.: An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat. Immunol. (2003) 4:702-707.
74. INOHARA N, OGURA Y, FONTALBA A et al.: Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem. (2003) 278:5509-5512.
75. GIRARDIN SE, BONECA IG, VIALA J et al.: Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J. Biol. Chem. (2003) 278:8869-8872.
76. TANABE T, CHAMAILLARD M, OGURA Y et al.: Regulatory regions and critical residues of NOD2 involved in muramyl dipeptide recognition. EMBO J. (2004) 23:1587-1597.
77. KOBAYASHI KS, CHAMAILLARD M, OGURA Y et al.: Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science (2005) 307:731-734.
78. ABBOTT DW, WILKINS A, ASARA JM, CANTLEY LC: The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr. Biol. (2004) 14:2217-2227.
79. HUGOT JP, CHAMAILLARD M, ZOUALI H et al.: Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature (2001) 411:599-603.
80. OGURA Y, BONEN DK, INOHARA N et al.: A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature (2001) 411:603-606.
81. AHMAD T, ARMUZZI A, BUNCE M et al.: The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology (2002) 122:854-866.
82. WATANABE T, KITANI A, MURRAY PJ, STROBER W: NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper Type 1 responses. Nat. Immunol. (2004) 5:800-808.
83. PAULEAU AL, MURRAY PJ: Role of nod2 in the response of macrophages to toll-like receptor agonists. Mol. Cell. Biol. (2003) 23:7531-7539.
84. MAEDA S, HSU LC, LIU H et al.: Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-1beta processing. Science (2005) 307:734-738.
85. PICARD C, PUEL A, BONNET M et al.: Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science (2003) 299:2076-2079.
86. MEDVEDEV AE, LENTSCHAT A, KUHNS DB et al.: Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J. Exp. Med. (2003) 198:521-531.
87. KU CL, YANG K, BUSTAMANTE J et al.: Inherited disorders of human Toll-like receptor signaling: immunological implications. Immunol. Rev. (2005) 203:10-20.
88. SMAHI A, COURTOIS G, VABRES P et al.: Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature (2000) 405:466-472.
89. PUEL A, PICARD C, KU CL, SMAHI A, CASANOVA JL: Inherited disorders of NF-kappaB-mediated immunity in man. Curr. Opin. Immunol. (2004) 16:34-41.
90. ORANGE JS, BRODEUR SR, JAIN A et al.: Deficient natural killer cell cytotoxicity in patients with IKK-gamma/ NEMO mutations. J. Clin. Invest. (2002) 109:1501-1509.
91. JAIN A, MA CA, LIU S, BROWN M, COHEN J, STROBER W: Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat. Immunol. (2001) 2:223-228.
92. COURTOIS G, SMAHI A, REICHENBACH J et al.: A hyperrrorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J. Clin. Invest. (2003) 112:1108-1115.
93. KAISHO T, AKIRA S: Regulation of dendritic cell function through toll-like receptors. Curr. Mol. Med. (2003) 3:759-771.
94. BACCALA R, KONO DH, THEOFILOPOULOS AN: Interferons as pathogenic effectors in autoimmunity. Immunol. Rev. (2005) 204:9-26.
95. KAISHO T, TAKEUCHI O, KAWAI T, HOSHINO K, AKIRA S: Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. (2001) 166:5688-5694.
96. RIFKIN IR, LEADBETTER EA, BUSCONI L, VIGLIANTI G, MARSHAK-ROTHSTEIN A: Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol. Rev. (2005) 204:27-42.
97. VIAU M, ZOUALI M: B-lymphocytes, innate immunity, and autoimmunity. Clin. Immunol. (2005) 114:17-26.
98. APPLEQUIST SE, WALLIN RP, LJUNGGREN HG: Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines. Int. Immunol. (2002) 14:1065-1074.
99. BOURKE E, BOSISIO D, GOLAY J, POLENTARUTTI N, MANTOVANI A: The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood (2003) 102:956-963.
100. LEADBETTER EA, RIFKIN IR, HOHLBAUM AM, BEAUDETTE BC, SHLOMCHIK MJ, MARSHAK-ROTHSTEIN A: Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature (2002) 416:603-607.
101. VIGLIANTI GA, LAU CM, HANLEY TM, MIKO BA, SHLOMCHIK MJ, MARSHAK-ROTHSTEIN A: Activation of autoreactive B cells by CpG dsDNA. Immunity (2003) 19:837-847.
102. PASARE C, MEDZHITOV R: Control of B-cell responses by Toll-like receptors. Nature (2005) 438:364-368.
103. KAWAI T, ADACHI O, OGAWA T, TAKEDA K, AKIRA S: Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity (1999) 11:115-122.
104. KAWAI T, TAKEUCHI O, FUJITA 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. (2001) 167:5887-5894.
105. YAMAMOTO M, SATO S, MORI K et al.: Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J. Immunol. (2002) 169:6668-6672.
106. YAMAMOTO M, SATO S, HEMMI H et al.: Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science (2003) 301:640-643.
107. HOEBE K, DU X, GEORGEL P et al.: Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature (2003) 424:743-748.
108. YAMAMOTO M, SATO S, HEMMI H et al.: TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. (2003) 4:1144-1150.
109. SHARMA S, TENOEVER BR, GRANDVAUX N, ZHOU GP, LIN R, HISCOTT J: Triggering the interferon antiviral response through an IKK-related pathway. Science (2003) 300:1148-1151.
110. FITZGERALD KA, MCWHIRTER SM, FAIA KL et al.: IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. (2003) 4:491-496.
111. MCWHIRTER SM, FITZGERALD KA, ROSAINS J, ROWE DC, GOLENBOCK DT, MANIATIS T: IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts. Proc. Natl. Acad. Sci. USA (2004) 101:233-238.
112. HEMMI H, TAKEUCHI O, SATO S et al.: The roles of two IkappaB kinase-related kinases in lipopolysaccharide and double stranded RNA signaling and viral infection. J. Exp. Med. (2004) 199:1641-1650.
113. PERRY AK, CHOW EK, GOODNOUGH JB, YEH WC, CHENG G: Differential requirement for TANK-binding kinase-1 in Type I interferon responses to toll-like receptor activation and viral infection. J. Exp. Med. (2004) 199:1651-1658.
114. MEYLAN E, BURNS K, HOFMANN K et al.: RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappaB activation. Nat. Immunol. (2004) 5:503-507.
115. SATO S, SUGIYAMA M, YAMAMOTO M et al.: Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIP) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J. Immunol. (2003) 171:4304-4310.
116. GOHDA J, MATSUMURA T, INOUE J: Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J. Immunol. (2004) 173:2913-2917.
117. BARCHET W, CELLA M, COLONNA M: Plasmacytoid dendritic cells-virus experts of innate immunity. Semin. Immunol. (2005) 17:253-261.
118. KAISHO T, AKIRA S: Pleiotropic function of Toll-like receptors. Microbes Infect. (2004) 6:1388-1394.
119. HEMMI H, KAISHO T, TAKEDA K, AKIRA S: The roles of Toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J. Immunol. (2003) 170:3059-3064.
120. HEIL F, HEMMI H, HOCHREIN H et al.: Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science (2004) 303:1526-1529.
121. HONDA K, YANAI H, NEGISHI H et al.: IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature (2005) 434:772-777.
122. KAWAI T, SATO S, ISHII KJ et al.: Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAP6. Nat. Immunol. (2004) 5:1061-1068.
123. HONDA K, YANAI H, MIZUTANI T et al.: Role of a transductional- transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc. Natl. Acad. Sci. USA (2004) 101:15416-15421.
124. UEMATSU S, SATO S, YAMAMOTO M et al.: Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction. J. Exp. Med. (2005) 201:915-923.
125. OGANESYAN G, SAHA SK, GUO B et al.: Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature (2006) 439(7073):208-211.
126. HACKER H, REDECKE V, BLAGOEV B et al.: Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature (2006) 439(7073):204-207.
127. LATZ E, SCHOENEMEYER A, VISINTIN A et al.: TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. (2004) 5:190-198.
128. YONEYAMA M, KIKUCHI M, NATSUKAWA T et al.: The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. (2004) 5:730-737.
129. KATO H, SATO S, YONEYAMA M et al.: Cell type-specific involvement of RIG-I in antiviral response. Immunity (2005) 23:19-28.
130. KANG DC, GOPALKRISHNAN RV, WU Q, JANKOWSKY E, PYLE AM, FISHER PB: mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc. Natl. Acad. Sci. USA (2002) 99:637-642.
131. KOVACSOVICS M, MARTINON F, MICHEAU O, BODMER JL, HOFMANN K, TSCHOPP J: Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr. Biol. (2002) 12:838-843.
132. ANDREJEVA J, CHILDS KS, YOUNG DF et al.: The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc. Natl. Acad. Sci. USA (2004) 101:17264-17269.
133. YONEYAMA M, KIKUCHI M, MATSUMOTO K et al.: Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. (2005) 175:2851-2858.
134. KAWAI T, TAKAHASHI K, SATO S et al.: IPS-1, an adaptor triggering RIG-I- and Mda5-mediated Type I interferon induction. Nat. Immunol. (2005) 6:981-988.
135. SETH RB, SUN L, EA CK, CHEN ZJ: identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell (2005) 122:669-682.
136. XU LG, WANG YY, HAN KJ, LI LY, ZHAI Z, SHU HB: VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell (2005) 19:727-740.
137. MEYLAN E, CURRAN J, HOFMANN K et al.: Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature (2005) 437:1167-1172.
138. YOSHIDA H, OKABE Y, KAWANE K, FUKUYAMA H, NAGATA S: Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat. Immunol. (2005) 6:49-56.
139. OKABE Y, KAWANE K, AKIRA S, TANIGUCHI T, NAGATA S: Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. (2005) 202:1333-1339.
140. ISHII KJ, COBAN C, KATO H et al.: A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. (2006) 7:40-48.