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Toll-Like Receptors in the Mammalian Innate Immune System

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Innate Immunity of Plants, Animals, and Humans

Part of the book series: Nucleic Acids and Molecular Biology ((NUCLEIC,volume 21))

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Toll-like receptors (TLRs) are evolutionary conserved, germ-line encoded molecules that express an ectodomain with leucine-rich regions, a single transmembrane domain, and a cytoplasmic region that contains the Toll-IL-1R resistance (TIR) signaling domain. TLRs recognize bacterial and viral pathogen-associated molecular patterns (PAMPs), as well as certain endogenous mammalian “danger signals,” i.e., proteins, oligosaacharides, and nucleic acids released from damaged cells as a consequence of stress, inflammation, and wounding. TLR2, TLR4, TLR5, TLR9, and TLR11 preferentially respond to bacterial, yeast, and protozoan PAMPs, while TLR3, TLR7, and TLR8 sense viral nucleic acids. TLRs exhibit different cellular localization: TLR2, TLR4, and TLR5 are expressed on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are localized intracellularly in endosomal compartments. Recognition of PAMPs by TLRs triggers TLR oligomerization and conformational changes within TIR domains, leading to recruitment of various adapter proteins and kinases. This, in turn, activates MAP kinases, transcription factors, and, ultimately, production of nitric oxide (NO) and reactive oxygen intermediates, up-regulation of expression of accessory and co-stimulatory molecules, and secretion of cytokines and chemokines. TLR-mediated up-regulation of co-stimulatory and MHC molecules on dendritic cells (DC), coupled with cytokine production and DC maturation, facilitates the adaptive immune response, providing a link between the innate and adaptive immunity. This review focuses on mechanisms of TLR signaling, known mutations/polymorphisms in genes encoding TLRs and IRAK-4 and their implication for susceptibility to infectious and autoimmune diseases and asthma.

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References

  • Abe T, Hemmi H, Miyamoto H, Moriishi K, Tamura S, Takaku H, Akira S, Matsuura Y (2005) Involvement of the Toll-like receptor 9 signaling pathway in the induction of innate immunity by baculovirus. J Virol 79:2847–2858

    Article  PubMed  CAS  Google Scholar 

  • Agnese DM, Calvano JE, Hahm SJ, Coyle SM, Corbett SA, Calvano SE, Lowry SF (2002) Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 186:1522–1525

    Article  PubMed  CAS  Google Scholar 

  • Ahmad-Nejad P, Kacker H, Rutz M, Bauer S, Vabulas RM, Wagner H (2002) Bacterial CpG-DNA and lipopolysaccharides activate Toll-like receptors at distinct cellular compartments. Eur J Immunol 32: 1958–1968

    Article  PubMed  CAS  Google Scholar 

  • Akira S, Takeda K (2004) Toll-like receptor signaling. Nat Rev Immunol 4:499–511

    Article  PubMed  CAS  Google Scholar 

  • Alexopoulou L, Holt AC, Medzhitov R, Flavell RA (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 413:732–738

    Article  PubMed  CAS  Google Scholar 

  • Ameziane N, Beillat T, Verpillat P, Chollet-Martin S, Aumont MC, Seknadji P, Lebret D, Ollivier V, Prost D de (2003) Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol 23:e61–e64

    Article  PubMed  CAS  Google Scholar 

  • Anderson KV, Bokla L, Nusslein-Volhard C (1985) Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798

    Article  PubMed  CAS  Google Scholar 

  • Arbibe L, Mira JP, Teusch N, Guha M, Macman N, Godowski PJ, Ulevitch RJ, Knaus UG (2000) Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol 1:533–540

    Article  PubMed  CAS  Google Scholar 

  • Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25:187–191

    Article  PubMed  CAS  Google Scholar 

  • Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  PubMed  CAS  Google Scholar 

  • Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB, Boukhvalova MS, Hemming VG, Blanco JCG, Vogel SN (2007) Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J Immunol (in press)

    Google Scholar 

  • Bell JK, Askins J, Hall PR, Davies DR, Segal DM (2006) The dsRNA binding site of human Toll-like receptor 3. Proc Natl Acad Sci USA 103:8792–8797

    Article  PubMed  CAS  Google Scholar 

  • Bellocchio S, Montagnoli C, Bozza S, Gaziano R, Rossi G, Mambula SS, Vecchi A, Mantovani A, Levits SM, Romani L (2004) The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol 172:3059–3069

    PubMed  CAS  Google Scholar 

  • Ben-Ali M, Barbouche MR, Bousnina S, Chabbou A, Dellagi K (2004) Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol 11:625–626

    PubMed  CAS  Google Scholar 

  • Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025–1029

    Article  PubMed  CAS  Google Scholar 

  • Blander JM, Medzhitov R (2004) Regulation of phagosome maturation by signals from toll-like receptors. Science 304:1014–1018

    Article  PubMed  CAS  Google Scholar 

  • Bulut Y, Faure E, Thomas L, Equilis O, Arditi M (2001) 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

    PubMed  CAS  Google Scholar 

  • Bulut Y, Faure E, Thomas L, Karahashi H, Michelsen KS, Equils O, Morrison SG, Arditi M (2002) Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol 168:1435–1440

    PubMed  CAS  Google Scholar 

  • Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer J-L, Di Marco F, French L, Tschopp J (1998) MyD88, an adaptor protein involved in IL-1 signaling. J Biol Chem 273:12203–12209

    Article  PubMed  CAS  Google Scholar 

  • Burns K, Cladworthy J, Martin L, Martinon F, Plumpton C, Maschera B, Lewis A, Ray K, Tschopp J, Volpe F (2000) Tollip, a new component of the IL-1RI pathway, links IRAK to the IL-1 receptor. Nat Cell Biol 2:346–351

    Article  PubMed  CAS  Google Scholar 

  • Buwitt-Beckmann U, Heine H, Wiesmuller KH, Jung G, Brock R, Akira S, Ulmer AJ (2006) TLR1- and TLR6-independent recognition of bacterial lipopeptides. J Biol Chem 281:9049–9057

    Article  PubMed  CAS  Google Scholar 

  • Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG (2006) The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 7:1074–1081

    Article  PubMed  CAS  Google Scholar 

  • Chen LY, Zuraw BL, Zhao M, Liu FT, Huang S, Pan ZK (2003) Involvement of protein tyrosine kinase in Toll-like receptor 4-mediated NF-kappa B activation in human peripheral blood monocytes. Am J Physiol Lung Cell Mol Physiol 284:L607–L613

    PubMed  CAS  Google Scholar 

  • Choe J, Kelker MS, Wilson IA (2005) Crystal structure of human toll-like receptor 3 (TLR3) ectodomain. Science 309:581–585

    Article  PubMed  CAS  Google Scholar 

  • Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F (1999) Toll-like receptor 4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 274:10689–10692

    Article  PubMed  CAS  Google Scholar 

  • Chuang T, Ulevitch RJ (2001) Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta 1518:157–161

    PubMed  CAS  Google Scholar 

  • Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ (2004) TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nat Immunol 5:488–494

    Article  PubMed  CAS  Google Scholar 

  • Da Silva Correia J, Soldau K, Christen U, Tobias PS, Ulevitch RJ (2001) Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex: transfer from CD14 to TLR4 and MD-2. J Biol Chem 276:21129–21135

    Article  PubMed  CAS  Google Scholar 

  • Day N, Tangsinmankong N, Ochs H, Rucker R, Picard C, Casanova JL, Haraguchi S, Good R (2004) Interleukin receptor-associated kinase (IRAK-4) deficiency associated with bacterial infections and failure to sustain antibody responses. J Pediatr 144:524–526

    Article  PubMed  Google Scholar 

  • Deng L, Wang C, Spencer E, Yang L, Braun A, You J, Slaughter C, Pickart C, Chen ZJ (2000) Activation of the IDB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103:351–361

    Article  PubMed  CAS  Google Scholar 

  • Dziarski R, Wang Q, Miyake K, Kirschning CJ, Gupta D (2001) MD-2 enables Toll-like receptor 2 (TLR2)-mediated responses to lipopolysaccharide and enhances TLR2-mediated responses to Gram-positive and Gram-negative bacteria and their cell wall components. J Immunol 166:1938–1944

    PubMed  CAS  Google Scholar 

  • Ea CK, Sun L, Inoue J, Chen ZJ (2004) TIFA activates IkappaB kinase (IKK) by promoting oligomerization and ubiquitination of TRAF6. Proc Natl Acad Sci USA 101:15318–15323

    Article  PubMed  CAS  Google Scholar 

  • Eder W, Klimecki W, Yu L, Mutius E von, Riedler J, Braun-Fahrander C, Nowak D, Martinez FD (2004) Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 113:482–488

    Article  PubMed  CAS  Google Scholar 

  • Faber J, Meyer CU, Gemmer C, Russo A, Finn A, Murdoch C, Zenz W, Mannhalter C, Zabel BU, Schmitt HJ, Habermehl P, Zepp F, Knuf M (2006) Human toll-like receptor 4 mutations are associated with susceptibility to invasive meningococcal disease in infancy. Pediatr Infect Dis J 25:80–81

    Article  PubMed  Google Scholar 

  • Fageras Bottcher M, Hmani-Aifa M, Lindstrom A, Jenmalm MC, Mai XM, Nilsson L, Zdolek HA, Bjorksten B, Soderkvist P, Vaarala O (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol 114:561–567

    Article  PubMed  CAS  Google Scholar 

  • Feterowski C, Emmanuilidis K, Miethke T, Gerauer K, Rump M, Ulm K, Holzmann B, Weighardt H (2003) Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis. Immunology 109:426–431

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald KA, Palsson-McDermott EM, Bowie AG, Jefferies CA, Mansell AS, Brady G, Brint E, Dunne A, Gray P, Harte MT, McMurray D, Smith DE, Sims JE, Bird TA, O’Neill LA (2001) Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 413:78–83

    Article  PubMed  CAS  Google Scholar 

  • Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT (2003) LPS-TLR4 signaling to IRF-3/7 and NF-kB involves the Toll adapters TRAM and TRIF. J Exp Med 198:1043–1055

    Article  PubMed  CAS  Google Scholar 

  • Flo TH, Ryan L, Latz E, Takeuchi O, Monks BG, Lien E, Halaas O, Akira S, Skjak-Braek, Golenbock DT, Espevik T (2002) Involvement of toll-like receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers. J Biol Chem 277:35489–3595

    Article  PubMed  CAS  Google Scholar 

  • Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J, Rutgeerts P (2004) Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut 53:987–992

    Article  PubMed  CAS  Google Scholar 

  • Genc MR, Vardhana S, Delaney ML, Onderdonk A, Tuomala R, Norwitz E, Witkin SS (2004) Relationship between a toll-like receptor-4 gene polymorphism, bacterial vaginosis-related flora and vaginal cytokine responses in pregnant women. Eur J Obstet Gynecol Reprod Biol 116:152–156

    Article  PubMed  CAS  Google Scholar 

  • Gewirtz AT, Navas TA, Lyons S, Godowski PJ, Madara JL (2001) Cutting edge: bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression. J Immunol 167:1882–1885

    PubMed  CAS  Google Scholar 

  • Golenbock DT, Liu Y, Millham FH, Freeman MW, Zoeller RA (1993) Surface expression of human CD14 in Chinese hamster ovary fibroblasts imparts macrophage-like responsiveness to bacterial endotoxin. J Biol Chem 268:22055–22059

    PubMed  CAS  Google Scholar 

  • Gray P, Dunne A, Brikos C, Jefferies CA, Doyle SL, O’Neill LA (2006) MyD88 adapter-like (Mal) is phosphorylated by Bruton’s tyrosine kinase during TLR2 and TLR4 signal transduction. J Biol Chem 281:10489–10495

    Article  PubMed  CAS  Google Scholar 

  • Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M (2002) Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J Immunol 168:5989–5992

    PubMed  CAS  Google Scholar 

  • Hacker H, Redecke V, Blagoev B, Kratchmarova I, Hsu LC, Wang GG, Kamps MP, Raz E, Wagner H, Hacker G, Mann M, Karin M (2006) Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature 439:204–207

    Article  PubMed  CAS  Google Scholar 

  • Hajjar AM, O’Mahony DS, Ozinsky A, Underhill DM, Aderem A, Klebanoff SJ, Wilson CB (2001) Cutting edge: functional interactions between toll-like receptor (TLR) 2 and TLR1 or TLR6 in response to phenol-soluble modulin. J Immunol 166:15–19

    PubMed  CAS  Google Scholar 

  • Hardy M, O’Neill L (2004) The murine Irak2 gene encodes four alternatively spliced isoforms, two of which are inhibitory. J Biol Chem 279:27669–27708

    Article  CAS  Google Scholar 

  • 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 MyD88. J Immunol 174:2942–2950

    PubMed  CAS  Google Scholar 

  • Hawn TR, Verbon A, Lettinga KD, Zhao LP, Li SS, Laws RJ, Skerret SJ, Beutler B, Schroeder L, Nachman A, Ozinsky A, Smith KD, Aderem A (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med 198:1563–1572

    Article  PubMed  CAS  Google Scholar 

  • Hawn TR, Verbon A, Janer M, Zhao LP, Beutler B, Aderem A (2005) Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc Natl Acad Sci USA 102:2487–2489

    Article  PubMed  CAS  Google Scholar 

  • 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 flagellin is mediated by Toll-like receptor 5. Nature 410:1099–10103

    Article  PubMed  CAS  Google Scholar 

  • Haziot A, Ferrero E, Kontgen F, Hijiya N, Yamomoto S, Silver J, Stewart CL, Goyert SM (1996) Resistance to endotoxin shock and reduced dissemination of Gram-negative bacteria in CD14-deficient mice. Immunity 4:407–414

    Article  PubMed  CAS  Google Scholar 

  • 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)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol 33:2987–2997

    Article  PubMed  CAS  Google Scholar 

  • Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529

    Article  PubMed  CAS  Google Scholar 

  • Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ (2000) Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and mouse Toll-like receptor 2. J Immunol 165:618–622

    PubMed  CAS  Google Scholar 

  • Hochrein H, Schlatter B, O’Keeffe M, Wagner C, Schmitz F, Schiemann M, Bauer S, Suter M, Wagner H (2004) Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci USA 101:11416–11421

    Article  PubMed  CAS  Google Scholar 

  • Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B (2003) Identification of Lps2 as a key transducer of MyD88-independent TLR signaling. Nature 424:743–748

    Article  PubMed  CAS  Google Scholar 

  • Hoebe K, George P, Rutschmann S, Du X, Mudd S, Crozat K, Sovath S, Shamet L, Hartung T, Zahringer U, Beutler B (2005) CD36 is a sensor of diacylglycerides. Nature 433:523–527

    Article  PubMed  CAS  Google Scholar 

  • Honda K, Yanai H, Mizutani T, Negishi H, Shimada N, Suzuki N, Ohba Y, Takaoka A, Yeh WC, Taniguchi T (2004) Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci USA 101:15416–14521

    Article  PubMed  CAS  Google Scholar 

  • Honda K, Ohba Y, Yanai H, Negishi H, Mizutani T, Takaoka A, Taya C, Taniguchi T (2005) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–1040

    Article  PubMed  CAS  Google Scholar 

  • Horng T, Barton GM, Medzhitov R (2001) TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol 2:835–841

    Article  PubMed  CAS  Google Scholar 

  • Horng T, Barton GM, Flavell RA, Medzhitov R (2002) The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420:329–333

    Article  PubMed  CAS  Google Scholar 

  • Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752

    PubMed  CAS  Google Scholar 

  • Inamori K, Ariki S, Kawabata S (2004) A Toll-like receptor in horseshoe crabs. Immunol Rev 198:106–115

    Article  PubMed  CAS  Google Scholar 

  • Ingalls RR, Monks BG, Savedra RJr, Christ WJ, Delude RL, Medvedev AE, Espevik T, Golenbock DT (1998) CD11/CD18 and CD14 share a common lipid A signaling pathway. J Immunol 161:5413–5420

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Iwasaki A, Medzhitov R (2004) Toll-like receptor control of the adaptive immune responses. Nat Immunol 5:987–995

    Article  PubMed  CAS  Google Scholar 

  • Jacobs H, Bross L (2001) Towards an understanding of somatic hypermutation. Curr Opin Immunol 13:208–218

    Article  PubMed  CAS  Google Scholar 

  • Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Jensen LE, Whitehead AS (2001) IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability. J Biol Chem 276:29037–29044

    Article  PubMed  CAS  Google Scholar 

  • Jensen LE, Whitehead AS (2003) Pellino2 activates the mitogen activated protein kinase pathway. FEBS Lett 545:199–202

    Article  PubMed  CAS  Google Scholar 

  • Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X (2002) Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol 22:7158–7167

    Article  PubMed  CAS  Google Scholar 

  • Jiang Z, Johnson HJ, Nie H, Qin J, Bird TA, Li X (2003) Pellino 1 is required for Interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex. J Biol Chem 278:10952–10956

    Article  PubMed  CAS  Google Scholar 

  • Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Huber M, Kalis C, Keck S, Galanos C, Freudenberg M, Beutler B (2005) CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6:565–570

    Article  PubMed  CAS  Google Scholar 

  • Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 3:499

    Article  PubMed  CAS  Google Scholar 

  • Kagan JC, Medzhitov R (2006) Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125:943–955

    Article  PubMed  CAS  Google Scholar 

  • Kaisho T, Akira S (2006) Toll-like receptor function and signaling. J Allergy Clin Immunol 117:979–987

    Article  PubMed  CAS  Google Scholar 

  • Kaisho T, Takeuchi O, Kawai T, Hoshino K, Akira S (2001) Endotoxin-induced maturation of MyD88-deficient dendritic cells. J Immunol 166:5688–5694

    PubMed  CAS  Google Scholar 

  • Kang TJ, Lee SB, Chae GT (2002) A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy. Cytokine 20:56–62

    Article  PubMed  CAS  Google Scholar 

  • Kang TJ, Yeum CE, Kim BC, You EY, Chae GT (2004) Differential production of interleukin-10 and interleukin-12 in mononuclear cells from leprosy patients with a Toll-like receptor 2 mutation. Immunology 112:674–680

    Article  PubMed  CAS  Google Scholar 

  • Kariko K, Ni H, Capodici J, Lamphier M, Weissman D (2004) mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 279:12542–12550

    Article  PubMed  CAS  Google Scholar 

  • 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 T, Akira S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105

    Article  PubMed  CAS  Google Scholar 

  • Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nat Immunol 7:131–137

    Article  PubMed  CAS  Google Scholar 

  • Kawai T, Adashi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115–122

    Article  PubMed  CAS  Google Scholar 

  • Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, Sato S, Hoshino K, Akira D (2001) 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 167:5887–94

    PubMed  CAS  Google Scholar 

  • Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, Williet J, Schwartz DA (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347:185–192

    Article  PubMed  CAS  Google Scholar 

  • Kilding R, Akil M, Till S, Amos R, Winfield J, Iiles MM, Wilson AG (2003) A biologically important single nucleotide polymorphism within the toll-like receptor-4 gene is not associated with rheumatoid arthritis. Clin Exp Rheumatol 21:340–342

    PubMed  CAS  Google Scholar 

  • Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA (2002) IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110:191–202

    Article  PubMed  CAS  Google Scholar 

  • Kollewe C, Mackensen AC, Neumann D, Knop J, Cao P, Wesche H, Martin MU (2004) Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. J Biol Chem 279:5227–5236

    Article  PubMed  CAS  Google Scholar 

  • Knopp J, Martin MU (1999) Effects of IL-1 receptor-associated kinase (IRAK) expression on IL-1 signaling are independent of its kinase activity. FEBS Lett 448:81–85

    Article  Google Scholar 

  • Kopp E, Medzhitov R, Carothers J, Xiao C, Douglas I, Janeway CA, Ghosh S (1999) ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev 13:2059–2071

    Article  PubMed  CAS  Google Scholar 

  • Kuhns DB, Long Priel DA, Gallin JI (1997) Endotoxin and IL-1 hyporesponsiveness in a patient with recurrent bacterial infections. J Immunol 158:3959–3964

    PubMed  CAS  Google Scholar 

  • Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT, erson LJ, et al (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory synsytial virus. Nat Immunol 1:398–401

    Article  PubMed  CAS  Google Scholar 

  • Lauw FN, Caffrey DR, Golenbock DT (2005) Of mice and man:TLR11 (finally) finds profilin. Trends Immunol 26:509–511

    Article  PubMed  CAS  Google Scholar 

  • Lazarus R, Klimecki WT, Raby BA, Vercelli D, Palmer LJ, Kwiatkowski DJ, Silverman EK, Martinez F, Weiss ST (2003) Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9):frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics 81:85–91

    Article  PubMed  CAS  Google Scholar 

  • Leadbetter EA, Rifkin IR, Hohlbaum AM, Beadette BC, Shlomnik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–607

    Article  PubMed  CAS  Google Scholar 

  • Lee H, Dunzendorfer S, Tobias PS (2004). Cytoplasmic domain-mediated dimerizations of Toll-like receptor 4 observed by β-lactamase enzyme fragment complementation J Biol Chem 279:10564

    Article  PubMed  CAS  Google Scholar 

  • Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983

    Article  PubMed  CAS  Google Scholar 

  • Li S, Strelow A, Fontana EJ, Wesche H (2002) IRAK-4:a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA 99:5567–5572

    Article  PubMed  CAS  Google Scholar 

  • Li X, Commane M, Burns C, Vithalani K, Cao Z, Stark GR (1999) Mutant cells that do not respond to interleukin-1 (IL-1) reveal a novel role for IL-1 receptor-associated kinase. Mol Cell Biol 19:4643–4652

    PubMed  CAS  Google Scholar 

  • Lien E, Sellati TJ, Yoshimura A, Flo TH, Rawadi G, Finberg RW, Carroll JD, Espevik T, Ingalls RR, Radolf JD, Golenbock DT (1999) Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J Biol Chem 274:33419–33425

    Article  PubMed  CAS  Google Scholar 

  • Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA (2000) A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 68:6398–6401

    Article  PubMed  CAS  Google Scholar 

  • Lorenz E, Mira JP, Frees KL, Schwartz DA (2002a) Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock. Arch Intern Med 162:1028–1032

    Article  PubMed  CAS  Google Scholar 

  • Lorenz E, Hallman M, Marttlia R, Haataja R, Schwartz DA (2002b) Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res 52:373–376

    PubMed  CAS  Google Scholar 

  • 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 USA 101:5598–5603

    Article  PubMed  CAS  Google Scholar 

  • Lye E, Mirtsos C, Suzuki N, Suzuki S, Yah WC (2004) The role of interleukin 1 receptor-associated kinase-4 (IRAK-4) kinase activity in IRAK-4-mediated signaling. J Biol Chem 279:40653–40658

    Article  PubMed  CAS  Google Scholar 

  • Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT (2003) Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci USA 100:1966–1971

    Article  PubMed  CAS  Google Scholar 

  • Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O’Neill LA, Hertzog PJ (2006) Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7:148–155

    Article  PubMed  CAS  Google Scholar 

  • Martin MU, Wesche H (2002) Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family. Biochim Biophys Acta 1592:265–280

    Article  PubMed  CAS  Google Scholar 

  • McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O’Neill LA (2006) Trif-related adapter molecule is phosphorylated by PKCvarepsilon during Toll-like receptor 4 signaling. Proc Natl Acad Sci USA 103:9196–9201

    Article  PubMed  CAS  Google Scholar 

  • Means TK, Lien E, Yoshimura A, Wang S, Golenbock DT, Fenton MJ (1999) The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. J Immunol 163:6748–6755

    PubMed  CAS  Google Scholar 

  • Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN (2003) Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med 198:521–531

    Article  PubMed  CAS  Google Scholar 

  • Medvedev AE, Thomas K, Awomoyi A, Kuhns DB, Gallin JI, Li X, Vogel SN (2005) Cutting edge: expression of IL-1 receptor-associated kinase-4 (IRAK-4) proteins with mutations identified in a patient with recurrent bacterial infections alters normal IRAK-4 interaction with components of the IL-1 receptor complex. J Immunol 174:6587–6591

    PubMed  CAS  Google Scholar 

  • Medvedev AE, Kuhns DB, Gallin JI, Vogel SN (2006) IRAK-4: a key kinase involved in toll-like receptor signaling and resistance to bacterial infection. In: O’Neill LAJ, Brint E (eds) Toll-like receptors in inflammation. Birkhäuser, Basel, pp 173–192

    Google Scholar 

  • Medvedev AE, Piao W, Shoenfelt J, Rhee SH, Chen H, Basu S, Wahl LM, Fenton MJ, Vogel SN (2007) Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. J Biol Chem 282:16042–16053

    Article  PubMed  CAS  Google Scholar 

  • Medzhitov R, Janeway C Jr (2000) Innate immunity. N Engl J Med 343:338–344

    Article  PubMed  CAS  Google Scholar 

  • Medzhitov R, Janeway C Jr (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Meijer AH, Gabby Krens SF, Medina Rodriguez IA, He S, Bitter W, Snaar-Jagalska B, Spaink HP (2004) Expression analysis of the Toll-like receptor and TIR domain adaptor families of zebrafish. Mol Immunol 40:773–83

    Article  PubMed  CAS  Google Scholar 

  • Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M, Tschopp J (2004) RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation. Nat Immunol 5:503–507

    Article  PubMed  CAS  Google Scholar 

  • Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A (2006) Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 7:569–575

    Article  PubMed  CAS  Google Scholar 

  • Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrardt S, Schroder NW, Bienzle U, Schumann RR (2006a) Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. Proc Natl Acad Sci USA 103:177–182

    Article  PubMed  CAS  Google Scholar 

  • Mockenhaupt FP, Hamann L, Gaertner C von, Bedu-Addo G, Kleinsorgen C von, Schumann RR, Bienzle U (2006b) Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis 194:184–188

    Article  PubMed  CAS  Google Scholar 

  • Moore CE, Segal S, Berendt AR, Hill AV, Day NP (2004) Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin Diagn Lab Immunol 11:1194–1197

    PubMed  CAS  Google Scholar 

  • Moore KJ, Andersson LP, Ingalls RR, Monks BG, Li R, Arnaout MA, Golenbock DR, Freeman MW (2000) Divergent response to LPS and bacteria in CD14-deficient murine macrophages. J Immunol 165:4272–4280

    PubMed  CAS  Google Scholar 

  • Morre SA, Murillo LS, Spaargaren J, Fennema HS, Pena AS (2002) Role of the toll-like receptor 4 Asp299Gly polymorphism in susceptibility to Candida albicans infection. J Infect Dis 186:1377–1379

    Article  PubMed  Google Scholar 

  • Morre SA, Murillo LS, Bruggeman CA, Pena AS (2003) The role that the functional Asp299Gly polymorphism in the toll-like receptor-4 gene plays in susceptibility to Chlamydia trachomatis-associated tubal infertility. J Infect Dis 187:341–342

    Article  PubMed  Google Scholar 

  • Muzio M, Ni J, Feng P, Dixit V (1997) IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science 278:1612–1615

    Article  PubMed  CAS  Google Scholar 

  • Nagai Y, Akashi S, Nagafuku M, Ogata M, Twakura Y, Akira S, Kitamura T, Kosugi A, Kimoto M, Miyake K (2002) Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 3:667–672

    PubMed  CAS  Google Scholar 

  • Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T, Honda K (2005) Negative regulation of Toll-like-receptor signaling by IRF-4. Proc Natl Acad Sci USA 102:15989–15994

    Article  PubMed  CAS  Google Scholar 

  • Newport MJ, Allen A, Awomoyi AA, Dunstan SJ, McKinney E, Marchant A, Sirugo G (2004) The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in the Gambia. Tuberculosis 84:347–352

    Article  PubMed  CAS  Google Scholar 

  • Noguchi E, Nishimura F, Fukai H, Kim J, Ichikawa K, Shibasaki M, Arinami T (2004) An association study of asthma and total serum immunoglobin E levels for Toll-like receptor polymorphisms in a Japanese population. Clin Exp Allergy 34:177–183

    Article  PubMed  CAS  Google Scholar 

  • Nusinzon I, Horvath CM (2006) Positive and negative regulation of the innate antiviral response and beta interferon gene expression by deacetylation. Mol Cell Biol 26:3106–3113

    Article  PubMed  CAS  Google Scholar 

  • Oganesyan G, Saha SK, Guo B, He JQ, Shahangian A, Zarnegar B, Perry A, Cheng G (2006) Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response. Nature 439:208–211

    Article  PubMed  CAS  Google Scholar 

  • Ogus AC, Yoldas B, Ozdemir T, Uguz A, Olcen S, Keser I, Coskun M, Cilli A, Yegin O (2004) The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J 23:219–223

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss JF (2001) The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 276:10229–10233

    Article  PubMed  CAS  Google Scholar 

  • O’Neill LA, Fitzgerald KA, Bowie AG (2003) The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 24:286–290

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Oshiumi H, Sasai M, Shida K, Fujita T, Matsumoto M, Seya T (2003b) TICAM-2: a bridging adapter recruiting to Toll-like receptor 4 TICAM-1 that induces interferon-β. J Biol Chem 278:49751–49762

    Article  PubMed  CAS  Google Scholar 

  • 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 defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 97:13766–13771

    Article  PubMed  CAS  Google Scholar 

  • Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377

    Article  PubMed  CAS  Google Scholar 

  • Perera P-Y, Vogel SN, Detore GR, Haziot A, Goyert SM (1997) CD14-dependent and CD14-independent signaling pathways in murine macrophages from normal and CD14 knockout mice stimulated with lipopolysaccharide or taxol. J Immunol 158:4422–4429

    PubMed  CAS  Google Scholar 

  • Perera PY, Mayadas TN, Takeuchi O, Akira S, Zaks-Zilberman M, Goyert SM, Vogel SN (2001) CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol 166:574–581

    PubMed  CAS  Google Scholar 

  • Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, Elbim C, Hitchcock R, Lammas D, Davies G, Al-Ghonaium A, Al- Rayes H, Al-Jumaah S, Al-Hajjar S, Al-Mohsen IZ, Frayha HH, Rucker R, Hawn TR, Aderem A, Tufenkeji H, Haraguchi S, Day NK, Good RA, Gougerot-Pocidalo MA, Ozinsky A, Casanova JL (2003) Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299:2076–2079

    Article  PubMed  CAS  Google Scholar 

  • Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088

    Article  PubMed  CAS  Google Scholar 

  • Puel A, Yamg K, Ku CL, von Bernuth H, Bustamante J, Santos OF, Lawrence T, Chang HH, Al-Mousa H, Picard C, Casanova JL (2005) Heritable defects of the human TLR signalling pathways. J Endotoxin Res 11:220–224

    PubMed  CAS  Google Scholar 

  • Pugin J, Heumann D, Tomasz A, Kravchenko VV, Akamatsu Y, Nishijima M, Glauser MP, Tobias PS, Ulevitch RJ (1994) CD14 as a pattern recognition receptor. Immunity 1:509–516

    Article  PubMed  CAS  Google Scholar 

  • Qin J, Jiang Z, Qian Y, Casanova J-L, Li X (2004) IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. J Biol Chem 279:26748–26753

    Article  PubMed  CAS  Google Scholar 

  • Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D (1999) Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189:615-2-65

    Article  PubMed  CAS  Google Scholar 

  • Raby BA, Klimecki WT, Laprise C, Renaud Y, Faith J, Lemire M, Greenwood C, Weiland KM, Lange C, Palmer LJ, Lazarus R, Vercelli D, Kwiatkowski DJ, Silverman EK, Martinez FD, Hudson TJ, Weiss ST (2002) Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes. Am J Respir Crit Care Med 166:1449–1456

    Article  PubMed  Google Scholar 

  • Rallabhandi P, Bell J, Boukhvalova MS, Medvedev A, Lorenz E, Arditi M, Hemming VG, Blanco JC, Segal DM, Vogel SN (2006) Analysis of TLR4 polymorphic variants: new insights into TLR4/MD-2/CD14 stoichiometry, structure, and signaling. J Immunol 177:322–332

    PubMed  CAS  Google Scholar 

  • Read RC, Pullin J, Gregory S, Borrow R, Kaczmarski EB, di Giovine FS, Dower SK, Cannings C, Wilson AG (2001) A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease. J Infect Dis 184:640–642

    Article  PubMed  CAS  Google Scholar 

  • Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, Schweighoffer E, Williams DL, Gordon S, Tybulewicz VL, Brown GD, Reis e Sousa C (2005) Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22:507–517

    Article  PubMed  CAS  Google Scholar 

  • Ronni T, Agarwal V, Haykinson M, Haberland ME, Cheng G, Smale ST (2003) Common interaction surfaces of the toll-like receptor 4 cytoplasmic domain stimulate multiple nuclear targets. Mol Cell Biol 23:2543–2555

    Article  PubMed  CAS  Google Scholar 

  • Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O’Neill LA, Fitzgerals KA, Golenbock DT (2006) The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction. Proc Natl Acad Sci USA 103:6299–6304

    Article  PubMed  CAS  Google Scholar 

  • Sackesen C, Karaaslan C, Keskin O, Tokol N, Tahan F, Civelek E, Sover OU, Adalioglu G, Tuncer A, Birben E, Oner C, Kalayci O (2005) The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy 60:1485–1492

    Article  PubMed  CAS  Google Scholar 

  • Sarkar SN, Peters KL, Elco CP, Sakamoto S, Pal S, Sen GC (2004) Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nat Struct Mol Biol 11:1060–1067

    Article  PubMed  CAS  Google Scholar 

  • Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K, Akira S (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) 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 171:4304–4310

    PubMed  CAS  Google Scholar 

  • Schmitt C, Humeny A, M. Becker C, Brune K, Pahl A (2002) Polymorphisms of TLR4: rapid genotyping and reduced response to lipopolysaccharide of TLR4 mutant alleles. Clin Chem 48:1661–1667

    PubMed  CAS  Google Scholar 

  • Schroder NW, Diterich I, Zinke A, Eckert J, Draing C, von Baehr V, Hassler D, Priem S, Hahn K, Michelsen KS, Hartung T, Burmester GR, Gobel UB, Hermann C, Schumann RR (2005) Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease. J Immunol 175:2534–2540

    PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782

    Article  PubMed  CAS  Google Scholar 

  • Smiley ST, King JA, Hancock VW (2001) Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol 167:2887–2894

    PubMed  CAS  Google Scholar 

  • Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, Beutler B (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci USA 100:6075–6080

    Article  PubMed  CAS  Google Scholar 

  • Stuart LM, Deng J, Silver JM, Takahashi K, Tseng AA, Hennessy EJ, Ezekowitz RA, Moore KJ (2005) Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J Cell Biol 170:477–485

    Article  PubMed  CAS  Google Scholar 

  • Suzuki N, Suzuki S, Duncan GS, Millar DG, Wada T, Mirtsos C, Takada H, Wakeham A, Itie A, Li S, Penninger JM, Wesche H, Ohashi PS, Mak TW, Yeh WC (2002) Severe impairment of interleukin-1 and Toll-like receptor signalling in mice lacking IRAK-4. Nature 416:750–756

    Article  PubMed  CAS  Google Scholar 

  • Suzuki N, Suzuki S, Millar DG, Unno M, Hara H, Calzascia T, Yamasaki S, Yokosuka T, Chen NJ, Elford AR, Suzuki J, Takeuchi A, Mirtsos C, Bouchard D, Ohashi PS, Yeh WC, Saito T (2006) A critical role for the innate immune signaling molecule IRAK-4 in T cell activation. Science 311:1927–1932

    Article  PubMed  CAS  Google Scholar 

  • Swantek JL, Tsen MF, Cobb M, Thomas JA (2000) IL-1 receptor-associated kinase modulates host responsiveness to endotoxin. J Immunol 164:4301–4306

    PubMed  CAS  Google Scholar 

  • Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K (2000) TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 5:649–658

    Article  PubMed  CAS  Google Scholar 

  • Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark G, Matsumoto M (2001) Interleukin-1 (IL-1) receptor-associated kinase leads to activation of tak 1 by inducing tab2 translocation in the IL-1 signaling pathway. Mol Cell Biol 21:2475–2484

    Article  PubMed  CAS  Google Scholar 

  • Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T (2005) Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434:243–249

    Article  PubMed  CAS  Google Scholar 

  • Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J (2003) Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling. J Biol Chem 278:12144–12150

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1–14

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K, Morr M, Muhlradt PF, Akira S (2000) Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J Immunol 164:554–557

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Tal G, Mandelberg A, Dalal I, Cesar K, Somekh E, Tal A, Oron A, Itskovich S, Ballin A, Houri S, Beigelman A, Lider O, Rechavi G, Amariglio N (2004) Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease. J Infect Dis 189:2057–2063

    Article  PubMed  CAS  Google Scholar 

  • Tapping RI, Tobias PS (2003) J Endotoxin Res 9:264–268

    PubMed  CAS  Google Scholar 

  • Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC (2002) Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J Exp Med 195:99–111

    Article  PubMed  CAS  Google Scholar 

  • Thomas JA, Allen JL, Tsen M, Dubnicoff T, Danao J, Liao XC, Cao Z, Wasserman SA (1999) Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. J Immunol 163:978–985

    PubMed  CAS  Google Scholar 

  • Travassos LH, Girardin SE, Philpott DJ, Blanot D, Nahori MA, Werts C, Boneca IG (2004) Toll-like receptor 2-dependent bacterial sensing does not occur via peptidoglycan recognition. EMBO Rep 5:1000–1006

    Article  PubMed  CAS  Google Scholar 

  • Tsan MF, Gao B (2004) Endogenous ligands of Toll-like receptors. J Leukoc Biol 76:514–519

    Article  PubMed  CAS  Google Scholar 

  • Uehori J, Matsumoto M, Tsuji S, Akazawa T, Takeuchi O, Akira S, Kawata T, Azuma I, Toyoshima K, Seya T (2003) Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette–Guerin peptidoglycan. Infect Immun 71:4238–4249

    Article  PubMed  CAS  Google Scholar 

  • Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F, Matsuda M, Coban C, Ishii KJ, Kawai T, Takeuchi O, Akira S (2005) 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 201:915–923

    Article  PubMed  CAS  Google Scholar 

  • Underhill DM, Ozinski A (2002) Toll-like receptors:key mediators of microbe detection. Curr Opin Immunol 14:103–110

    Article  PubMed  CAS  Google Scholar 

  • Vabulas RM, Ahmad-Nejad P, Costa C da, Miethke T, Kirschning CJ, Hacker H, Wagner H (2001) Endocytosed HSP60s use toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J Biol Chem 276:31332–31339

    Article  PubMed  CAS  Google Scholar 

  • Vabulas RM, Braedel S, Hilf N, Singh-Jasuja H, Herter S, Ahmas-Nejad P, Kirschning CJ, Da Costa C, Rammensee HG, Wagner H, Schild H (2002a) The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway. J Biol Chem 277:20847–20853

    Article  PubMed  CAS  Google Scholar 

  • Vabulas RM, Ahmad-Nejad P, Ghose S, Kirschning CJ, Issels RD, Wagner H (2002b) HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J Biol Chem 277:15107–15112

    Article  PubMed  CAS  Google Scholar 

  • Vasselon T, Detmers PA, Charron D, Haziot A (2004) TLR2 recognizes a bacterial lipopeptide through direct binding. J Immunol 173:7401–7405

    PubMed  CAS  Google Scholar 

  • Viriyakosol S, Tobias PS, Kitchens RL, Kirkland TN (2001) MD-2 binds to bacterial lipopolysaccharide. J Biol Chem 276:38044–38051

    PubMed  CAS  Google Scholar 

  • Viriyakosol S, Fierer J, Brown GD, Kirkland TN (2005) Innate immunity to the pathogenic fungus Coccidioides posadasii is dependent on the Toll-like receptor 2 and dectin-1. Infect Immun 73:1553–1560

    Article  PubMed  CAS  Google Scholar 

  • Visintin A, Latz E, Monks BG, Espevik T, Golenbock DT (2003) Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction. J Biol Chem 278:48313–48320

    Article  PubMed  CAS  Google Scholar 

  • Vogel S, Hirschfeld MJ, Perera PY (2001) Signal integration in lipopolysaccharide (LPS)-stimulated murine macrophages. J Endotoxin Res 7:237–241

    PubMed  CAS  Google Scholar 

  • Vogel SN, Fitzgerald KA, Fenton MJ (2003) TLRs: differential adapter utilization by toll-like receptors mediates TLR-specific patterns of gene expression. Mol Interv 3:466–477

    Article  PubMed  CAS  Google Scholar 

  • Vogel SN, Awomoyi AA, Rallabhandi P, Medvedev AE (2005) Mutations in TLR4 signaling that lead to increased susceptibility to infection in humans: an overview. J Endotoxin Res 11:333–339

    PubMed  CAS  Google Scholar 

  • Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ (2001) TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412:346–351

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251

    Article  PubMed  CAS  Google Scholar 

  • Wesche H, Henzel WJ, Shillinglaw W, Li S, Cao Z (1997) MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7:837–847

    Article  PubMed  CAS  Google Scholar 

  • Wesche H, Gao X, Li X, Kirschning CJ, Stark GR, Cao Z (1999) IRAK-M is a novel member of the pelle/interleukin-1 receptor associated kinase (IRAK) family. J Biol Chem 274:19403–19410

    Article  PubMed  CAS  Google Scholar 

  • Wietek C, O’Neill L (2002) IRAK-4: a new drug target in inflammation, sepsis, and autoimmunity. Mol Interv 2:212–215

    Article  PubMed  CAS  Google Scholar 

  • Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431–1433

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T, Hoshino K, Takeuchi O, Kobayashi M, Fujita T, Takeda K, Akira S (2002a) Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324–329

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Mori K, Hoshino K, Takeuchi O, Takeda K, Akira S (2002b) 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 169:6668–6672

    PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003a) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003b) TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto M, Takeda K, Akira S (2004) TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol 40:861–868

    Article  PubMed  CAS  Google Scholar 

  • Yamin T-T, Miller DK (1997) The interleukin-1 receptor-associated kinase is degraded by proteosomes following its phosphorylation. J Biol Chem 272:21540–21547

    Article  PubMed  CAS  Google Scholar 

  • Yang H, Young DW, Gusovsky F, Chow JC (2000) Cellular events mediated by lipopolysaccharide-stimulated Toll-like receptor 4: MD-2 is required for activation of mitogen-activated protein kinases and Elk-1. J Biol Chem 275:20861–20866

    Article  PubMed  CAS  Google Scholar 

  • Yang IA, Barton SJ, Rorke S, Cakebread JA, Keith TP, Clough JB, Holgate ST, Holloway JW (2004) Toll-like receptor 4 polymorphism and severity of atopy in asthmatics. Genes Immun 5:41–45

    Article  PubMed  CAS  Google Scholar 

  • 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 profilin-like protein. Science 308:1626–1629

    Article  PubMed  CAS  Google Scholar 

  • Yoshida H, Jono H, Kai H, Li JD (2005) The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. J Biol Chem 280:41111–41121

    Article  PubMed  CAS  Google Scholar 

  • 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, cytokines. J Immunol 168:554–561

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore (UMB), 660 W. Redwood Street, Rm. HH 324, Baltimore, MD 21201, USA

    Andrei E. Medvedev & Stefanie N. Vogel

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  1. Andrei E. Medvedev
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  2. Stefanie N. Vogel
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  1. Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, 23845, Borstel, Germany

    Holger Heine

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Medvedev, A.E., Vogel, S.N. (2008). Toll-Like Receptors in the Mammalian Innate Immune System. In: Heine, H. (eds) Innate Immunity of Plants, Animals, and Humans. Nucleic Acids and Molecular Biology, vol 21. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-73930-2_7

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