Toll-like receptors: Ligands, cell-based models, and readouts for receptor action

Methods in Molecular Biology

Volumn 1390, Issue , 2016, Pages 3-27

  Dowling, Jennifer K ^a   Dellacasagrande, Jérome ^a  

^a NONE

Author keywords

Cell based assays; Reporter gene assays; TLR ligands; Toll like receptors; Whole blood assays

Indexed keywords

LIGAND; TOLL LIKE RECEPTOR; TRANSCRIPTION FACTOR;

BLOOD ANALYSIS; CELL ASSAY; HUMAN; NONHUMAN; REPORTER GENE; SIGNAL TRANSDUCTION; ANIMAL; CELL CULTURE TECHNIQUE; CELL LINE; GENE EXPRESSION; GENETICS; METABOLISM; PHOSPHORYLATION; PROTEIN TRANSPORT;

ANIMALS; CELL CULTURE TECHNIQUES; CELL LINE; GENE EXPRESSION; GENES, REPORTER; HUMANS; LIGANDS; PHOSPHORYLATION; PROTEIN TRANSPORT; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS; TRANSCRIPTION FACTORS;

EID: 84956542049     PISSN: 10643745     EISSN: None     Source Type: Book Series    
DOI: 10.1007/978-1-4939-3335-8_1     Document Type: Chapter

References (147)

1. Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14
2. Gay NJ, Keith FJ (1991) Drosophila Toll and IL-1 receptor. Nature 351:355–356
3. Brikos C, O'Neill LA (2008) Signalling of Toll-like receptors. Handb Exp Pharmacol 183:21–50
4. Gay NJ, Gangloff M, Weber AN (2006) Tolllike receptors as molecular switches. Nat Rev Immunol 6:693–698
5. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825
6. Boehme KW, Compton T (2004) Innate sensing of viruses by toll-like receptors. J Virol 78:7867–7873
7. Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511
8. Barton GM, Kagan JC, Medzhitov R (2006) Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 7:49–56
9. Saitoh S, Akashi S, Yamada T, Tanimura N, Kobayashi M, Konno K, Matsumoto F, Fukase K, Kusumoto S, Nagai Y, Kusumoto Y, Kosugi A, Miyake K (2004) Lipid A antagonist, lipid IVa, is distinct from lipid A in interaction with Toll-like receptor 4 (TLR4)-MD-2 and ligand-induced TLR4 oligomerization. Int Immunol 16:961–969
10. Botos I, Liu L, Wang Y, Segal DM, Davies DR (2009) The toll-like receptor 3:dsRNA signaling complex. Biochim Biophys Acta 1789:667–674
11. Wang Y, Liu L, Davies DR, Segal DM (2010) Dimerization of Toll-like receptor 3 (TLR3) is required for ligand binding. J Biol Chem 285:36836–36841
12. Liu L, Botos I, Wang Y, Leonard JN, Shiloach J, Segal DM, Davies DR (2008) Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science 320:379–381
13. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik SG, Lee H, Lee JO (2007) Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell 130:1071–1082
14. Kim HM, Park BS, Kim JI, Kim SE, Lee J, Oh SC, Enkhbayar P, Matsushima N, Lee H, Yoo OJ, Lee JO (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell 130:906–917
15. Yoon SI, Kurnasov O, Natarajan V, Hong M, Gudkov AV, Osterman AL, Wilson IA (2012) Structural basis of TLR5-fl agellin recognition and signaling. Science 335:859–864
16. Tanji H, Ohto U, Shibata T, Miyake K, Shimizu T (2013) Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science 339:1426–1429
17. Nyman T, Stenmark P, Flodin S, Johansson I, Hammarstrom M, Nordlund P (2008) The crystal structure of the human toll-like receptor 10 cytoplasmic domain reveals a putative signaling dimer. J Biol Chem 283:11861–11865
18. Gangloff M, Weber AN, Gay NJ (2005) Conserved mechanisms of signal transduction by Toll and Toll-like receptors. J Endotoxin Res 11:294–298
19. Nunez Miguel R, Wong J, Westoll JF, Brooks HJ, O'Neill LA, Gay NJ, Bryant CE, Monie TP (2007) A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specifi c scaffold for the recruitment of signalling adaptor proteins. PLoS One 2, e788
20. Akira S, Yamamoto M, Takeda K (2003) Role of adapters in Toll-like receptor signalling. Biochem Soc Trans 31:637–642
21. Lu YC, Yeh WC, Ohashi PS (2008) LPS/ TLR4 signal transduction pathway. Cytokine 42:145–151
22. Kaisho T, Akira S (2006) Toll-like receptor function and signaling. J Allergy Clin Immunol 117:979–987, quiz 988
23. Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S (2002) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324–329
24. Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9
25. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88- defi cient mice to endotoxin. Immunity 11:115–122
26. Stack J, Doyle SL, Connolly DJ, Reinert LS, O'Keeffe KM, McLoughlin RM, Paludan SR, Bowie AG (2014) TRAM is required for TLR2 endosomal signaling to type I IFN induction. J Immunol 193(12):6090–6102
27. Volpi C, Fallarino F, Pallotta MT, Bianchi R, Vacca C, Belladonna ML, Orabona C, De Luca A, Boon L, Romani L, Grohmann U, Puccetti P (2013) High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway. Nat Commun 4:1852
28. Hennessy EJ, Parker AE, O'Neill LA (2010) Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 9:293–307
29. Gay NJ, Gangloff M (2007) Structure and function of Toll receptors and their ligands. Annu Rev Biochem 76:141–165
30. Rutz M, Metzger J, Gellert T, Luppa P, Lipford GB, Wagner H, Bauer S (2004) Tolllike receptor 9 binds single-stranded CpGDNA in a sequence- and pH-dependent manner. Eur J Immunol 34:2541–2550
31. Oldenburg M, Kruger A, Ferstl R, Kaufmann A, Nees G, Sigmund A, Bathke B, Lauterbach H, Suter M, Dreher S, Koedel U, Akira S, Kawai T, Buer J, Wagner H, Bauer S, Hochrein H, Kirschning CJ (2012) TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modifi cation. Science 337:1111–1115
32. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin RL, Akira S (2002) Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol 169:10–14
33. Hasan UA, Dollet S, Vlach J (2004) Differential induction of gene promoter constructs by constitutively active human TLRs. Biochem Biophys Res Commun 321:124–131
34. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801
35. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ (1999) Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 274:17406–17409
36. Sandor F, Latz E, Re F, Mandell L, Repik G, Golenbock DT, Espevik T, Kurt-Jones EA, Finberg RW (2003) Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling. J Cell Biol 162:1099–1110
37. Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A, Ishizaka A, Abraham E (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290:C917–C924
38. Flo TH, Halaas O, Lien E, Ryan L, Teti G, Golenbock DT, Sundan A, Espevik T (2000) Human toll-like receptor 2 mediates monocyte activation by Listeria monocytogenes but not by group B streptococci or lipopolysaccharide. J Immunol 164(4):2064–2069
39. Ozinsky A, Underhill DM, Fontenot JD, Hajjar AM, Smith KD, Wilson CB, Schroeder L, Aderem A (2000) The repertoire for pattern recognition of pathogens by the innate immune system is defi ned by cooperation between toll-like receptors. Proc Natl Acad Sci U S A 97:13766–13771
40. Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jehanno M, Viala J, Tedin K, Taha MK, Labigne A, Zahringer U, Coyle AJ, DiStefano PS, Bertin J, Sansonetti PJ, Philpott DJ (2003) Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 300:1584–1587
41. de Bouteiller O, Merck E, Hasan UA, Hubac S, Benguigui B, Trinchieri G, Bates EE, Caux C (2005) Recognition of double-stranded RNA by human toll-like receptor 3 and downstream receptor signaling requires multimerization and an acidic pH. J Biol Chem 280(46):38133–38145
42. Marshall-Clarke S, Downes JE, Haga IR, Bowie AG, Borrow P, Pennock JE, Grencis RK, Rothwell P (2007) Polyinosinic acid is a ligand for toll-like receptor 3. J Biol Chem 282(34):24759–24766
43. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita C, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105
44. Zhou Y, Guo M, Wang X, Li J, Wang Y, Ye L, Dai M, Zhou L, Persidsky Y, Ho W (2013) TLR3 activation effi ciency by high or low molecular mass poly I:C. Innate Immun 19:184–192
45. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397
46. Caroff M, Karibian D (2003) Structure of bacterial lipopolysaccharides. Carbohydr Res 338:2431–2447
47. Coats SR, Reife RA, Bainbridge BW, Pham TT, Darveau RP (2003) Porphyromonas gingivalis lipopolysaccharide antagonizes Escherichia coli lipopolysaccharide at toll-like receptor 4 in human endothelial cells. Infect Immun 71:6799–6807
48. Huber M, Kalis C, Keck S, Jiang ZF, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Beutler B, Galanos C, Freudenberg MA (2006) R-form LPS, the master key to the activation of TLR4/MD-2-positive cells. Eur J Immunol 36:701–711
49. Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC (2007) The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 316:1628–1632
50. Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ (2000) Cutting edge: repurifi cation of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J Immunol 165:618–622
51. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M (2001) Involvement of TLR4/MD-2 complex in species-specifi c lipopolysaccharide-mimetic signal transduction by Taxol. J Endotoxin Res 7:232–236
52. Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS, Oliveira MF, Oliveira PL, Graca-Souza AV, Bozza MT (2007) Characterization of heme as activator of toll-like receptor 4. J Biol Chem 282:20221–20229
53. Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6:823–835
54. Matzinger P (2002) The danger model: a renewed sense of self. Science 296:301–305
55. Gao B, Tsan MF (2003) Recombinant human heat shock protein 60 does not induce the release of tumor necrosis factor alpha from murine macrophages. J Biol Chem 278:22523–22529
56. Ohashi K, Burkart V, Flohe S, Kolb H (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor- 4 complex. J Immunol 164:558–561
57. Smith KD, Andersen-Nissen E, Hayashi F, Strobe K, Bergman MA, Barrett SL, Cookson BT, Aderem A (2003) Toll-like receptor 5 recognizes a conserved site on fl agellin required for protofi lament formation and bacterial motility. Nat Immunol 4:1247–1253
58. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, Eng JK, Akira S, Underhill DM, Aderem A (2001) The innate immune response to bacterial fl agellin is mediated by Toll-like receptor 5. Nature 410:1099–1103
59. Okusawa T, Fujita M, Nakamura J, Into T, Yasuda M, Yoshimura A, Hara Y, Hasebe A, Golenbock DT, Morita M, Kuroki Y, Ogawa T, Shibata K (2004) Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6. Infect Immun 72:1657–1665
60. Triantafi lou M, Gamper FG, Haston RM, Mouratis MA, Morath S, Hartung T, Triantafi lou K (2006) Membrane sorting of toll-like receptor (TLR) -2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J Biol Chem 281:31002–31011
61. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531
62. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specifi c recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529
63. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, Flavell RA (2004) Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci U S A 101
64. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200
65. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, Wagner H, Bauer S (2003) The Toll-like receptor 7 (TLR7)-specifi c stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33:2987–2997
66. Kobold S, Wiedemann G, Rothenfusser S, Endres S (2014) Modes of action of TLR7 agonists in cancer therapy. Immunotherapy 6:1085–1095
67. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, Endres S, Hartmann G (2005) Sequencespecifi c potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med 11:263–270
68. Savarese E, Chae OW, Trowitzsch S, Weber G, Kastner B, Akira S, Wagner H, Schmid RM, Bauer S, Krug A (2006) U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7. Blood 107:3229–3234
69. Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS (2006) Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifi ers and polyT oligodeoxynucleotides. J Immunol 177:6584–6587
70. Krieg AM (2006) Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discov 5:471–484
71. Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G et al (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8(5):487–496
72. Magnusson M, Tobes R, Sancho J, Pareja E (2007) Cutting edge: natural DNA repetitive extragenic sequences from gram-negative pathogens strongly stimulate TLR9. J Immunol 179:31–35
73. Boule MW, Broughton C, Mackay F, Akira S, Marshak-Rothstein A, Rifkin IR (2004) Tolllike receptor 9-dependent and -independent dendritic cell activation by chromatinimmunoglobulin G complexes. J Exp Med 199:1631–1640
74. Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, Monks BG, McKnight CJ, Lamphier MS, Duprex WP, Espevik T, Golenbock DT (2007) Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8:772–779
75. Lenert P (2005) Inhibitory oligodeoxynucleotides–therapeutic promise for systemic autoimmune diseases? Clin Exp Immunol 140:1–10
76. Kalantari P, DeOliveira RB, Chan J, Corbett Y, Rathinam V, Stutz A, Latz E, Gazzinelli RT, Golenbock DT, Fitzgerald KA (2014) Dual engagement of the NLRP3 and AIM2 infl ammasomes by plasmodium-derived hemozoin and DNA during malaria. Cell Rep 6:196–210
77. Hasan U, Chaffois C, Gaillard C, Saulnier V, Merck E, Tancredi S, Guiet C, Briere F, Vlach J, Lebecque S, Trinchieri G, Bates EE (2005) Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through {MyD} 88. J Immunol 174:2942–2950
78. Govindaraj RG, Manavalan B, Lee G, Choi S (2010) Molecular modeling-based evaluation of hTLR10 and identifi cation of potential ligands in Toll-like receptor signaling. PLoS One 5, e12713
79. Oosting M, Cheng SC, Bolscher JM, Vestering-Stenger R, Plantinga TS, Verschueren IC, Arts P, Garritsen A, van Eenennaam H, Sturm P, Kullberg BJ, Hoischen A, Adema GJ, van der Meer JW, Netea MG, Joosten LA (2014) Human TLR10 is an anti-infl ammatory patternrecognition receptor. Proc Natl Acad Sci U S A 111:E4478–E4484
80. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S (2004) A toll-like receptor that prevents infection by uropathogenic bacteria. Science 303:1522–1526
81. Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A (2005) TLR11 activation of dendritic cells by a protozoan profi lin-like protein. Science 308:1626–1629
82. Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 102:9577–9582
83. Andrade WA, Souza Mdo C, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, Bartholomeu DC, Ghosh S, Golenbock DT, Gazzinelli RT (2013) Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host Microbe 13:42–53
84. Mishra BB, Gundra UM, Teale JM (2008) Expression and distribution of Toll-like receptors 11–13 in the brain during murine neurocysticercosis. J Neuroinfl ammation 5:53
85. Latz E, Visintin A, Lien E, Fitzgerald KA, Monks BG, Kurt-Jones EA, Golenbock DT, Espevik T (2002) Lipopolysaccharide rapidly traffi cs to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem 277:47834–47843
86. Yang RB, Mark MR, Gray A, Huang A, Xie MH, Zhang M, Goddard A, Wood WI, Gurney AL, Godowski PJ (1998) Toll-like receptor-2 mediates lipopolysaccharide- induced cellular signalling. Nature 395:284–288
87. Pridmore AC, Wyllie DH, Abdillahi F, Steeghs L, van der Ley P, Dower SK, Read RC (2001) A lipopolysaccharide-defi cient mutant of Neisseria meningitidis elicits attenuated cytokine release by human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. J Infect Dis 183:89–96
88. Matsuguchi T, Takagi K, Musikacharoen T, Yoshikai Y (1999) Gene expressions of lipopolysaccharide receptors, toll-like receptors 2 and 4, are differently regulated in mouse T lymphocytes. Blood 95(56):1378–1385
89. Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D (1999) Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J Immunol 163:1–5
90. Hasan UA, Trinchieri G, Vlach J (2005) Tolllike receptor signaling stimulates cell cycle entry and progression in fi broblasts. J Biol Chem 280:20620–20627
91. Wang J, Shao Y, Bennett TA, Shankar RA, Wightman PD, Reddy LG (2006) The functional effects of physical interactions among Toll-like receptors 7, 8, and 9. J Biol Chem 281:37427–37434
92. Takeshita F, Leifer CA, Gursel I, Ishii KJ, Takeshita S, Gursel M, Klinman DM (2001) Cutting edge: role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 167:3555–3558
93. Watanabe N, Narita M, Yamahira A, Nakamura T, Tochiki N, Saitoh A, Kaji M, Hashimoto S, Furukawa T, Toba K, Fuse I, Aizawa Y, Takahashi M (2010) Transformation of dendritic cells from plasmacytoid to myeloid in a leukemic plasmacytoid dendritic cell line (PMDC05). Leuk Res 34:1517–1524
94. Chaperot L, Blum A, Manches O, Lui G, Angel J, Molens JP, Plumas J (2006) Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells. J Immunol 176:248–255
95. Maeda T, Murata K, Fukushima T, Sugahara K, Tsuruda K, Anami M, Onimaru Y, Tsukasaki K, Tomonaga M, Moriuchi R, Hasegawa H, Yamada Y, Kamihira S (2005) A novel plasmacytoid dendritic cell line, CAL-1 established from a patient with blastic natural killer, cell lymphoma. Int J Hematol 81:148–154
96. Tapping RI, Orr SL, Lawson EM, Soldau K, Tobias PS (1999) Membrane-anchored forms of lipopolysaccharide (LPS)-binding protein do not mediate cellular responses to LPS independently of CD14. J Immunol 162:5483–5487
97. InvivoGen (2006) InvivoGen Insight Newsletter: TLR7 and TLR8. http://www.InvivoGen.com/docs/Insight200609.pdf
98. Park EK, Jung HS, Yang HI, Yoo MC, Kim C, Kim KS (2007) Optimized THP-1 differentiation is required for the detection of responses to weak stimuli. Infl amm Res 56:45–50
99. Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561
100. Chanput W, Mes JJ, Wichers HJ (2014) THP-1 cell line: an in vitro cell model for immune modulation approach. Int Immunopharmacol 23:37–45
101. Hippenstiel S, Opitz B, Schmeck B, Suttorp N (2006) Lung epithelium as a sentinel and effector system in pneumonia—molecular mechanisms of pathogen recognition and signal transduction. Respir Res 7:97
102. Jego G, Bataille R, Geffroy-Luseau A, Descamps G, Pellat-Deceunynck C (2006) Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through Toll-like receptors. Leukemia 20:1130–1137
103. Sha Q, Truong-Tran AQ, Plitt JR, Beck LA, Schleimer RP (2004) Activation of airway epithelial cells by toll-like receptor agonists. Am J Respir Cell Mol Biol 31:358–364
104. Ma Y, Li J, Chiu I, Wang Y, Sloane JA, Lu J, Kosaras B, Sidman RL, Volpe JJ, Vartanian T (2006) Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J Cell Biol 175:209–215
105. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G (2002) 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
106. Applequist SE, Wallin RP, Ljunggren HG (2002) Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines. Int Immunol 14:1065–1074
107. Nagase H, Okugawa S, Ota Y, Yamaguchi M, Tomizawa H, Matsushima K, Ohta K, Yamamoto K, Hirai K (2003) Expression and function of Toll-like receptors in eosinophils: activation by Toll-like receptor 7 ligand. J Immunol 171:3977–3982
108. Komai-Koma M, Jones L, Ogg GS, Xu D, Liew FY (2004) TLR2 is expressed on activated T cells as a costimulatory receptor. Proc Natl Acad Sci U S A 101:3029–3034
109. Hemont C, Neel A, Heslan M, Braudeau C, Josien R (2013) Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. J Leukoc Biol 93:599–609
110. Siren J, Pirhonen J, Julkunen I, Matikainen S (2005) IFN-alpha regulates TLR-dependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29. J Immunol 174:1932
111. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: Toll-like receptor 4 (TLR4) -defi cient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:6686–6687
112. Kurt-Jones EA, Sandor F, Ortiz Y, Bowen GN, Counter SL, Wang TC, Finberg RW (2004) Use of murine embryonic fi broblasts to defi ne Toll-like receptor activation and specifi city. J Endotoxin Res 10:419–424
113. Thurm CW, Halsey JF (2005) Measurement of cytokine production using whole blood. Curr Protoc Immunol Unit 7:18B
114. Blimkie D, Fortuno ES III, Yan H, Cho P, Ho K, Turvey SE, Marchant A, Goriely S, Kollmann TR (2011) Variables to be controlled in the assessment of blood innate immune responses to Toll-like receptor stimulation. J Immunol Methods 366:89–99
115. Hermann C, von Aulock S, Dehus O, Keller M, Okigami H, Gantner F, Wendel A, Hartung T (2006) Endogenous cortisol determines the circadian rhythm of lipopolysaccharide— but not lipoteichoic acid—inducible cytokine release. Eur J Immunol 36:371–379
116. Petrovsky N, Harrison LC (1995) Cytokinebased human whole blood assay for the detection of antigen-reactive T cells. J Immunol Methods 186:37–46
117. Schindler S, Asmus S, von Aulock S, Wendel A, Hartung T, Fennrich S (2004) Cryopreservation of human whole blood for pyrogenicity testing. J Immunol Methods 294:89–100
118. Smolen KK, Cai B, Gelinas L, Fortuno ES III, Larsen M, Speert DP, Chamekh M, Cooper PJ, Esser M, Marchant A, Kollmann TR (2014) Single-cell analysis of innate cytokine responses to pattern recognition receptor stimulation in children across four continents. J Immunol 193:3003–3012
119. Burl S, Townend J, Njie-Jobe J, Cox M, Adetifa UJ, Touray E, Philbin VJ, Mancuso C, Kampmann B, Whittle H, Jaye A, Flanagan KL, Levy O (2011) Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. PLoS One 6, e18185
120. Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR (2004) Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 173:4627–4634
121. Labuda LA, de Jong SE, Meurs L, Amoah AS, Mbow M, Ateba-Ngoa U, van der Ham AJ, Knulst AC, Yazdanbakhsh M, Adegnika AA (2014) Differences in innate cytokine responses between European and African children. PLoS One 9, e95241
122. Deitschel SJ, Kerl ME, Chang CH, DeClue AE (2010) Age-associated changes to pathogen- associated molecular patterninduced infl ammatory mediator production in dogs. J Vet Emerg Crit Care (San Antonio) 20:494–502
123. Figueiredo MD, Moore JN, Vandenplas ML, Sun WC, Murray TF (2008) Effects of the second-generation synthetic lipid A analogue E5564 on responses to endotoxin in [corrected] equine whole blood and monocytes. Am J Vet Res 69:796–803
124. Karper JC, Ewing MM, de Vries MR, de Jager SC, Peters EA, de Boer HC, van Zonneveld AJ, Kuiper J, Huizinga EG, Brondijk TH, Jukema JW, Quax PH (2013) TLR accessory molecule RP105 (CD180) is involved in post- interventional vascular remodeling and soluble RP105 modulates neointima formation. PLoS One 8, e67923
125. Chen YW, Smith ML, Sheets MP, Ballaron SJ, Trevillyan JM, Fey TA, Gauvin DM, Kolano R, Pong MS, Hsieh GC, Bauch J, Marsh K, Carter G, Luly J, Djuric S, Mollison KW (1999) Ex vivo assessment of immunosuppression in undiluted whole blood from pigs dosed with tacrolimus (FK506). Clin Immunol 90:133–140
126. Dietsch GN, Dipalma CR, Eyre RJ, Pham TQ, Poole KM, Pefaur NB, Welch WD, Trueblood E, Kerns WD, Kanaly ST (2006) Characterization of the infl ammatory response to a highly selective PDE4 inhibitor in the rat and the identifi cation of biomarkers that correlate with toxicity. Toxicol Pathol 34:39–51
127. Duffy D, Rouilly V, Libri V, Hasan M, Beitz B, David M, Urrutia A, Bisiaux A, Labrie ST, Dubois A, Boneca IG, Delval C, Thomas S, Rogge L, Schmolz M, Quintana-Murci L, Albert ML, Milieu Interieur Consortium (2014) Functional analysis via standardized whole-blood stimulation systems defi nes the boundaries of a healthy immune response to complex stimuli. Immunity 40:436–450
128. O'Neill LA, Bowie AG (2007) The family of fi ve: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364
129. Hansen MC, Nederby L, Henriksen MO, Hansen M, Nyvold CG (2014) Sensitive ligand-based protein quantifi cation using immuno-PCR: a critical review of singleprobe and proximity ligation assays. Biotechniques 56:217–228
130. Pranada AL, Metz S, Herrmann A, Heinrich PC, Muller-Newen G (2004) Real time analysis of STAT3 nucleocytoplasmic shuttling. J Biol Chem 279:15114–15123
131. Schindler U, Baichwal VR (1994) Three NF-kappa B binding sites in the human E-selectin gene required for maximal tumor necrosis factor alpha-induced expression. Mol Cell Biol 14:5820–5831
132. Johnson CM, Tapping RI (2007) Microbial products stimulate human Toll-like receptor 2 expression through histone modifi cation surrounding a proximal NF-kappaB-binding site. J Biol Chem 282:31197–31205
133. Berger J, Hauber J, Hauber R, Geiger R, Cullen BR (1988) Secreted placental alkaline phosphatase: a powerful new quantitative indicator of gene expression in eukaryotic cells. Gene 66:1–10
134. Markova SV, Golz S, Frank LA, Kalthof B, Vysotski ES (2004) Cloning and expression of cDNA for a luciferase from the marine copepod Metridia longa. A novel secreted bioluminescent reporter enzyme. J Biol Chem 279:3212–3217
135. Zhou S, Cerny AM, Bowen G, Chan M, Knipe DM, Kurt-Jones EA, Finberg RW (2010) Discovery of a novel TLR2 signaling inhibitor with anti-viral activity. Antiviral Res 87:295–306
136. Ehrhardt C, Kardinal C, Wurzer WJ, Wolff T, von Eichel-Streiber C, Pleschka S, Planz O, Ludwig S (2004) Rac1 and PAK1 are upstream of IKK-epsilon and TBK-1 in the viral activation of interferon regulatory factor- 3. FEBS Lett 567:230–238
137. Civas A, Genin P, Morin P, Lin R, Hiscott J (2006) Promoter organization of the interferon- A genes differentially affects virusinduced expression and responsiveness to TBK1 and IKKepsilon. J Biol Chem 281:4856–4866
138. Monteith GR, Bird GS (2005) Techniques: high-throughput measurement of intracellular Ca(2+)—back to basics. Trends Pharmacol Sci 26:218–223
139. National Center for Biotechnology Information (NCBI) (2015) http://www.ncbi.nlm.nih.gov/pcassay/?term=tlr
140. Reindl M, Lutterotti A, Ingram J, Schanda K, Gassner C, Deisenhammer F, Berger T, Lorenz E (2003) Mutations in the gene for toll-like receptor 4 and multiple sclerosis. Tissue Antigens 61:85–88
141. Karima R, Matsumoto S, Higashi H, Matsushima K (1999) The molecular pathogenesis of endotoxic shock and organ failure. Mol Med Today 5:123–132
142. Mansson A, Adner M, Hockerfelt U, Cardell LO (2006) A distinct Toll-like receptor repertoire in human tonsillar B cells, directly activated by PamCSK R-837 and CpG-2006 stimulation. Immunology 118:539–548
143. Caron G, Duluc D, Fremaux I, Jeannin P, David C, Gascan H, Delneste Y (2005) Direct stimulation of human T cells via TLR5 and TLR7/8: fl agellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol 175:1551–1557
144. Tabiasco J, Devevre E, Rufer N, Salaun B, Cerottini JC, Speiser D, Romero P (2006) Human effector CD8+ T lymphocytes express TLR3 as a functional coreceptor. J Immunol 177:8708–8713
145. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, Liu YJ (2001) Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869
146. Hart OM, Athie-Morales V, O'Connor GM, Gardiner CM (2005) TLR7/8-mediated activation of human NK cells results in accessory cell-dependent IFN-gamma production. J Immunol 175:1636–1642
147. Ito T, Wang YH, Liu YJ (2005) Plasmacytoid dendritic cell precursors/type I interferonproducing cells sense viral infection by Tolllike receptor (TLR) 7 and TLR9. Springer Semin Immunopathol 26:221–229