Skip to main content
SpringerLink
Log in

Signalling of Toll-Like Receptors

  • Chapter
Toll-Like Receptors (TLRs) and Innate Immunity

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 183))

Since Toll-like receptor (TLR) signaling was found crucial for the activation of innate and adaptive immunity, it has been the focus of immunological research. There are at least 13 identified mammalian TLRs, to date, that share similarities in their extracellular and intracellular domains. A vast number of ligands have been identified that are specifically recognized by different TLRs. As a response the TLRs dimerize and their signaling is initiated. The molecular basis of that signaling depends on the conserved part of their intracellular domain; namely the Toll/IL-1 receptor (TIR) domain. Upon TLR dimerization a TIR-TIR structure is formed that can recruit TIR-containing intracellular proteins that mediate their signaling. For this reason these proteins are named adapters. There are five adapters identified so far named myeloid differentiation primary response protein 88 (MyD88), MyD88-adapter like (Mal) or TIR domain-containing adapter (TIRAP), TIR domain-containing adapter inducing interferon-β (IFN-β) (TRIF) or TIR-containing adapter molecule-1 (TICAM-1), TRIF-related adapter molecule (TRAM) or TICAM-2, and sterile α and HEAT-Armadillo motifs (SARM). The first four play a fundamental role in TLR-signaling, defining which pathways will be activated, depending on which of these adapters will be recruited by each TLR. Among these adapter proteins MyD88 and TRIF are now considered as the signaling ones and hence the TLR pathways can be categorized as MyD88-dependent and TRIF-dependent.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, Nakanishi K, Akira S (1998) Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9: 143-150

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • An H, Zhao W, Hou J, Zhang Y, Xie Y, Zheng Y, Xu H, Qian C, Zhou J, Yu Y, Liu S, Feng G, Cao X (2006) SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 25: 919-928

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Bauer S, Kirschning CJ, Hacker H, Redecke V, Hausmann S, Akira S, Wagner H, Lipford GB (2001) Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci USA 98: 9237-9242

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Bell JK, Botos I, Hall PR, Askins J, Shiloach J, Segal DM, Davies DR (2005) The molecular structure of the Toll-like receptor 3 ligand-binding domain. Proc Natl Acad Sci USA 102: 10976-10980

    Article  CAS  PubMed  Google Scholar 

  • Bird TA, Gearing AJ, Saklatvala J (1988) Murine interleukin 1 receptor. Direct identification by ligand blotting and purification to homogeneity of an interleukin 1-binding glycoprotein. J Biol Chem 263: 12063-12069

    CAS  PubMed  Google Scholar 

  • Bonnert TP, Garka KE, Parnet P, Sonoda G, Testa JR, Sims JE (1997) The cloning and characterization of human MyD88: A member of an IL-1 receptor related family. FEBS Lett 402: 81-84

    Article  CAS  PubMed  Google Scholar 

  • Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, McNally E, Pickart C, Ma A (2004) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5: 1052-1060

    Article  CAS  PubMed  Google Scholar 

  • Brikos C, Wait R, Begum S, O’Neill LA, Saklatvala J (2007) Mass spectrometric analysis of the endogenous IL-1RI signalling complex formed after IL-1 binding identifies IL-1RAcP, MyD88 and IRAK-4 as the stable components. Mol Cell Proteomics

    Google Scholar 

  • Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O’Neill LA, Liew FY (2004) ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5: 373-379

    Article  CAS  PubMed  Google Scholar 

  • Brockman JA, Scherer DC, McKinsey TA, Hall SM, Qi X, Lee WY, Ballard DW (1995) Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappaB activation. Mol Cell Biol 15: 2809-2818

    CAS  PubMed  Google Scholar 

  • Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U (1995) Control of I kappa B-alpha proteolysis by site-specific, signal-induced phosphorylation. Science 267: 1485-1488

    Article  CAS  PubMed  Google Scholar 

  • Burns K, et al (1998) MyD88, an adapter protein involved in interleukin-1 signalling. J Biol Chem 273: 12203-12209

    Article  CAS  PubMed  Google Scholar 

  • Burns K, Janssens S, Brissoni B, Olivos N, Beyaert R, Tschopp J (2003) Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med 197: 263-268

    Article  PubMed  Google Scholar 

  • Cao Z, Henzel WJ, Gao X (1996a) IRAK: A kinase associated with the interleukin-1 receptor. Science 271: 1128-1131

    Article  CAS  Google Scholar 

  • Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV (1996b) TRAF6 is a signal transducer for interleukin-1. Nature 383: 443-446

    Article  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  CAS  PubMed  Google Scholar 

  • Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7: 758-765

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Cohen L, Henzel WJ, Baeuerle PA (1998) IKAP is a scaffold protein of the IkappaB kinase complex. Nature 395: 292-296

    Article  CAS  PubMed  Google Scholar 

  • Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ (2004) TLRindependent 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  CAS  PubMed  Google Scholar 

  • Covert MW, Leung TH, Gaston JE, Baltimore D (2005) Achieving stability of lipopolysaccharideinduced NF-kappaB activation. Science 309: 1854-1857

    Article  CAS  PubMed  Google Scholar 

  • Croston GE, Cao Z, Goeddel DV (1995) NF-kappa B activation by interleukin-1 (IL-1) requires an IL-1 receptor-associated protein kinase activity. J Biol Chem 270: 16514-16517

    Article  CAS  PubMed  Google Scholar 

  • Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA (2005) Rip1 mediates the Trif-dependent Toll-like receptor 3- and 4-induced NF-kappaB activation but does not contribute to interferon regulatory factor 3 activation. J Biol Chem 280: 36560-36566

    Article  CAS  PubMed  Google Scholar 

  • De Trez C, Pajak B, Brait M, Glaichenhaus N, Urbain J, Moser M, Lauvau G, Muraille E (2005) TLR4 and Toll-IL-1 receptor domain-containing adapter-inducing IFN-beta, but not MyD88, regulate Escherichia coli-induced dendritic cell maturation and apoptosis in vivo. J Immunol 175: 839-846

    CAS  PubMed  Google Scholar 

  • Delhase M, Hayakawa M, Chen Y, Karin M (1999) Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 284: 309-313

    Article  CAS  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 IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 103: 351-361

    Article  CAS  PubMed  Google Scholar 

  • DiDonato J, Mercurio F, Rosette C, Wu-Li J, Suyang H, Ghosh S, Karin M (1996) Mapping of the inducible IkappaB phosphorylation sites that signal its ubiquitination and degradation. Mol Cell Biol 16: 1295-1304

    CAS  PubMed  Google Scholar 

  • DiDonato JA, Mercurio F, Karin M (1995) Phosphorylation of I kappa B alpha precedes but is not sufficient for its dissociation from NF-kappa B. Mol Cell Biol 15: 1302-1311

    CAS  PubMed  Google Scholar 

  • Dinarello CA (1994) The interleukin-1 family: 10 years of discovery. Faseb J 8: 1314-1325

    CAS  PubMed  Google Scholar 

  • Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87: 2095-2147

    CAS  PubMed  Google Scholar 

  • Dower SK, Kronheim SR, March CJ, Conlon PJ, Hopp TP, Gillis S, Urdal DL (1985) Detection and characterization of high affinity plasma membrane receptors for human interleukin 1. J Exp Med 162: 501-515

    Article  CAS  PubMed  Google Scholar 

  • Doyle SL, Jefferies CA, O’Neill LA (2005) Bruton’s tyrosine kinase is involved in p65-mediated transactivation and phosphorylation of p65 on serine 536 during NFkappaB activation by lipopolysaccharide. J Biol Chem 280: 23496-23501

    Article  CAS  PubMed  Google Scholar 

  • Dunne A, Ejdeback M, Ludidi PL, O’Neill LA, Gay NJ (2003) Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88. J Biol Chem 278: 41443-41451

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald KA, Chen ZJ (2006) Sorting out Toll signals. Cell 125: 834-836

    Article  CAS  PubMed  Google Scholar 

  • Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T (2003a) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4: 491-496

    Article  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Gautam JK, Ashish, Comeau LD, Krueger JK, Smith MF, Jr. (2006) Structural and functional evidence for the role of the TLR2 DD loop in TLR1/TLR2 heterodimerization and signaling. J Biol Chem 281: 30132-30142

    Article  CAS  PubMed  Google Scholar 

  • Gay NJ, Keith FJ (1991) Drosophila Toll and IL-1 receptor. Nature 351: 355-356

    Article  CAS  PubMed  Google Scholar 

  • Gohda J, Matsumura T, Inoue J (2004) 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 173: 2913-2917

    CAS  PubMed  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  CAS  PubMed  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 

  • Han KJ, Su X, Xu LG, Bin LH, Zhang J, Shu HB (2004) Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways. J Biol Chem 279: 15652-15661

    Article  CAS  PubMed  Google Scholar 

  • Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, Smith GL, Bowie A, O’Neill LA (2003) The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med 197: 343-351

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto C, Hudson KL, Anderson KV (1988) The Toll gene of Drosophila, required for dorsalventral embryonic polarity, appears to encode a transmembrane protein. Cell 52: 269-279

    Article  CAS  PubMed  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: 1099-1103

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Hirotani T, Yamamoto M, Kumagai Y, Uematsu S, Kawase I, Takeuchi O, Akira S (2005) Regulation of lipopolysaccharide-inducible genes by MyD88 and Toll/IL-1 domain containing adaptor inducing IFN-beta. Biochem Biophys Res Commun 328: 383-392

    Article  CAS  PubMed  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  CAS  PubMed  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 TIR signalling. Nature

    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  CAS  PubMed  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: 15416-15421

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • Hu Y, Baud V, Delhase M, Zhang P, Deerinck T, Ellisman M, Johnson R, Karin M (1999) Abnormal morphogenesis but intact IKK activation in mice lacking the IKKalpha subunit of IkappaB kinase. Science 284: 316-320

    Article  CAS  PubMed  Google Scholar 

  • Huang J, Liu T, Xu LG, Chen D, Zhai Z, Shu HB (2005) SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. EMBO J 24: 4018-4028

    Article  CAS  PubMed  Google Scholar 

  • Hultmark D (1994) Macrophage differentiation marker MyD88 is a member of the Toll/IL-1 re-ceptor family. Biochem Biophys Res Commun 199: 144-146

    Article  CAS  PubMed  Google Scholar 

  • Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, Walch E, Wirth T, O’Neill LA (2003) Bruton’s tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. J Biol Chem 278: 26258-26264

    Article  CAS  PubMed  Google Scholar 

  • Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW (2005) Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11: 1173-1179

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Georgel P, Li C, Choe J, Crozat K, Rutschmann S, Du X, Bigby T, Mudd S, Sovath S, Wilson IA, Olson A, Beutler B (2006) Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proc Natl Acad Sci USA 103: 10961-10966

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Mak TW, Sen G, Li X (2004) Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta. Proc Natl Acad Sci USA 101: 3533-3538

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K, Li X (2002) Interleukin-1 (IL-1) receptorassociated 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kaiser WJ, Offermann MK (2005) Apoptosis induced by the Toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol 174: 4942-4952

    CAS  PubMed  Google Scholar 

  • Kamon H, Kawabe T, Kitamura H, Lee J, Kamimura D, Kaisho T, Akira S, Iwamatsu A, Koga H, Murakami M, Hirano T (2006) TRIF-GEFH1-RhoB pathway is involved in MHCII expression on dendritic cells that is critical for CD4 T-cell activation. EMBO J 25: 4108-4119

    Article  CAS  PubMed  Google Scholar 

  • Kariko K, Bhuyan P, Capodici J, Weissman D (2004) Small interfering RNAs mediate sequenceindependent gene suppression and induce immune activation by signaling through Toll-like receptor 3. J Immunol 172: 6545-6549

    CAS  PubMed  Google Scholar 

  • Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annu Rev Immunol 18: 621-663

    Article  CAS  PubMed  Google Scholar 

  • Kawagoe T, Sato S, Jung A, Yamamoto M, Matsui K, Kato H, Uematsu S, Takeuchi O, Akira S (2007) Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor-mediated immune responses but not in TCR signaling. J Exp Med 204: 1013-1024

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Sato S, Ishii KJ, Coban C, Hemmi H, Yamamoto M, Terai K, Matsuda M, Inoue J, Uematsu S, Takeuchi O, Akira S (2004) Interferon-alpha induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol 5: 1061-1068

    Article  CAS  PubMed  Google Scholar 

  • Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ, Kyrieleis O, Khan A, Aucan C, Segal S, Moore CE, Knox K, Campbell SJ, Lienhardt C, Scott A, Aaby P, Sow OY, Grignani RT, Sillah J, Sirugo G, Peshu N, Williams TN, Maitland K, Davies RJ, Kwiatkowski DP, Day NP, Yala D, Crook DW, Marsh K, Berkley JA, O’Neill LA, Hill AV (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria, and tuberculosis. Nat Genet 39: 523-528

    Article  CAS  PubMed  Google Scholar 

  • Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, Yoshida H, Kubo M, Yoshimura A (2002) SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17: 583-591

    Article  CAS  PubMed  Google Scholar 

  • Knop 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  CAS  PubMed  Google Scholar 

  • Knop J, Wesche H, Lang D, Martin MU (1998) Effects of overexpression of IL-1 receptorassociated kinase on NFkappaB activation, IL-2 production and stress-activated protein kinases in the murine T cell line EL4. Eur J Immunol 28: 3100-3109

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kollewe C, Mackensen AC, Neumann D, Knop J, Cao P, Li S, 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  CAS  PubMed  Google Scholar 

  • Koziczak-Holbro M, Joyce C, Gluck A, Kinzel B, Muller M, Tschopp C, Mathison JC, Davis CN, Gram H (2007) IRAK-4 kinase activity is required for interleukin-1 (IL-1) receptor- and Toll-like receptor 7-mediated signaling and gene expression. J Biol Chem 282: 13552-13560

    Article  CAS  PubMed  Google Scholar 

  • Lasker MV, Nair SK (2006) Intracellular TLR signaling: A structural perspective on human disease. J Immunol 177: 11-16

    CAS  PubMed  Google Scholar 

  • Le Page C, Popescu O, Genin P, Lian J, Paquin A, Galipeau J, Hiscott J (2001) Disruption of NFkappa B signaling and chemokine gene activation by retroviral mediated expression of IKK gamma/NEMO mutants. Virology 286: 422-433

    Article  CAS  PubMed  Google Scholar 

  • Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik 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  CAS  PubMed  Google Scholar 

  • Lee FS, Peters RT, Dang LC, Maniatis T (1998) MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proc Natl Acad Sci USA 95: 9319-9324

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Chuang TH, Redecke V, She L, Pitha PM, Carson DA, Raz E, Cottam HB (2003) Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci USA 100: 6646-6651

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Li C, Zienkiewicz J, Hawiger J (2005) Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1beta signaling pathway. J Biol Chem 280: 26152-26159

    Article  CAS  PubMed  Google Scholar 

  • Li Q, Lu Q, Hwang JY, Buscher D, Lee KF, Izpisua-Belmonte JC, Verma IM (1999a) IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev 13: 1322-1328

    Article  CAS  Google Scholar 

  • Li Q, Van Antwerp D, Mercurio F, Lee KF, Verma IM (1999b) Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284: 321-325

    Article  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  CAS  PubMed  Google Scholar 

  • Li X, Commane M, Burns C, Vithalani K, Cao Z, Stark GR (1999c) 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

    CAS  Google Scholar 

  • Li XH, Fang X, Gaynor RB (2001) Role of IKKgamma/NEMO in assembly of the Ikappa B kinase complex. J Biol Chem 276: 4494-4500

    Article  CAS  PubMed  Google Scholar 

  • Liberati NT, Fitzgerald KA, Kim DH, Feinbaum R, Golenbock DT, Ausubel FM (2004) Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response. Proc Natl Acad Sci USA 101: 6593-6598

    Article  CAS  PubMed  Google Scholar 

  • Liljeroos M, Vuolteenaho R, Morath S, Hartung T, Hallman M, Ojaniemi M (2007) Bruton’s tyrosine kinase together with PI 3-kinase are part of Toll-like receptor 2 multiprotein complex and mediate LTA induced Toll-like receptor 2 responses in macrophages. Cell Signal 19: 625-633

    Article  CAS  PubMed  Google Scholar 

  • Lord KA, Abdollahi A, Hoffman-Liebermann B, Liebermann DA (1990a) Dissection of the immediate early response of myeloid leukemia cells to terminal differentiation and growth inhibitory stimuli. Cell Growth Differ 1: 637-645

    CAS  Google Scholar 

  • Lord KA, Hoffman-Liebermann B, Liebermann DA (1990b) Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL6. Oncogene 5: 1095-1097

    CAS  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Lye E, Mirtsos C, Suzuki N, Suzuki S, Yeh 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  CAS  PubMed  Google Scholar 

  • Mansell A, Brint E, Gould JA, O’Neill LA, Hertzog PJ (2004) Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-kappaB activation by Toll-like receptor (TLR)-2 and TLR4. J Biol Chem 279: 37227-37230

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Martin M, Bol GF, Eriksson A, Resch K, Brigelius-Flohe R (1994) Interleukin-1-induced activation of a protein kinase co-precipitating with the type I interleukin-1 receptor in T cells. Eur J Immunol 24: 1566-1571

    Article  CAS  PubMed  Google Scholar 

  • Maschera B, Ray K, Burns K, Volpe F (1999) Overexpression of an enzymically inactive interleukin-1-receptor-associated kinase activates nuclear factor-kappa B. Bio chem J 339: 227-231

    CAS  Google Scholar 

  • May MJ, Marienfeld RB, Ghosh S (2002) Characterization of the Ikappa B-kinase NEMO binding domain. J Biol Chem 277: 45992-46000

    Article  CAS  PubMed  Google Scholar 

  • McCoy SL, Kurtz SE, Macarthur CJ, Trune DR, Hefeneider SH (2005) Identification of a peptide derived from vaccinia virus A52R protein that inhibits cytokine secretion in response to TLRdependent signaling and reduces in vivo bacterial-induced inflammation. J Immunol 174: 3006-3014

    CAS  PubMed  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 PKC{varepsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci USA 103: 9196-9201

    Article  CAS  PubMed  Google Scholar 

  • Medzhitov R, Preston-Hurlburt P, Kopp E, Stadlen A, Chen C, Ghosh S, Janeway CA (1998) MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 2: 253-258

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Mink M, Fogelgren B, Olszewski K, Maroy P, Csiszar K (2001) A novel human gene (SARM) at chromosome 17q11 encodes a protein with a SAM motif and structural similarity to Armadillo/beta-catenin that is conserved in mouse, Drosophila, and Caenorhabditis elegans. Genomics 74: 234-244

    Article  CAS  PubMed  Google Scholar 

  • Muzio M, Natoli G, Saccani S, Levrero M, Mantovani A (1998) The human Toll signaling pathway: divergence of nuclear factor kappaB and JNK/SAPK activation upstream of tumor necrosis factor receptor-associated factor 6 (TRAF6). J Exp Med 187: 2097-2101

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Naiki Y, Michelsen KS, Zhang W, Chen S, Doherty TM, Arditi M (2005) Transforming growth factor-beta differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. J Biol Chem 280: 5491-5495

    Article  CAS  PubMed  Google Scholar 

  • Nakagawa R, Naka T, Tsutsui H, Fujimoto M, Kimura A, Abe T, Seki E, Sato S, Takeuchi O, Takeda K, Akira S, Yamanishi K, Kawase I, Nakanishi K, Kishimoto T (2002) SOCS-1 participates in negative regulation of LPS responses. Immunity 17: 677-687

    Article  CAS  PubMed  Google Scholar 

  • Negishi H, Fujita Y, Yanai H, Sakaguchi S, Ouyang X, Shinohara M, Takayanagi H, Ohba Y, Taniguchi T, Honda K (2006) Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc Natl Acad Sci USA 103: 15136-15141

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • OMahony A, Lin X, Geleziunas R, Greene WC (2000) Activation of the heterodimeric Ikappa B kinase alpha (IKKalpha)-IKKbeta complex is directional: IKKalpha regulates IKKbeta under both basal and stimulated conditions. Mol Cell Biol 20: 1170-1178

    Article  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

    CAS  PubMed  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-beta induction. Nat Immunol 4: 161-167

    Article  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-beta. J Biol Chem

    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  CAS  PubMed  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, AlJumaah 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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Qin J, Jiang Z, Qian Y, Casanova JL, 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  CAS  PubMed  Google Scholar 

  • Qureshi ST, Lariviere L, Leveque G, Clermont S, Moore KJ, Gros P, Malo D (1999) Endotoxintolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med 189: 615-625

    Article  CAS  PubMed  Google Scholar 

  • Rosati O, Martin MU (2002) Identification and characterization of murine IRAK-2. Biochem Biophys Res Commun 297: 52-58

    Article  CAS  PubMed  Google Scholar 

  • Rothwarf DM, Zandi E, Natoli G, Karin M (1998) IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature 395: 297-300

    Article  CAS  PubMed  Google Scholar 

  • Rottenberg S, Schmuckli-Maurer J, Grimm S, Heussler VT, Dobbelaere DA (2002) Characterization of the bovine IkappaB kinases (IKK)alpha and IKKbeta, the regulatory subunit NEMO and their substrate IkappaBalpha. Gene 299: 293-300

    Article  CAS  PubMed  Google Scholar 

  • Rowe DC, McGettrick AF, Latz E, Monks BG, Gay NJ, Yamamoto M, Akira S, O’Neill LA, Fitzgerald 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  CAS  PubMed  Google Scholar 

  • Ruckdeschel K, Pfaffinger G, Haase R, Sing A, Weighardt H, Hacker G, Holzmann B, Heesemann J (2004) Signaling of apoptosis through TLRs critically involves toll/IL-1 receptor domain-containing adapter inducing IFN-beta, but not MyD88, in bacteria-infected murine macrophages. J Immunol 173: 3320-3328

    CAS  PubMed  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 receptorassociated 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

    CAS  PubMed  Google Scholar 

  • Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 177: 1272-1281

    CAS  PubMed  Google Scholar 

  • Su X, Li S, Meng M, Qian W, Xie W, Chen D, Zhai Z, Shu HB (2006) TNF receptor-associated factor-1 (TRAF1) negatively regulates Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling. Eur J Immunol 36: 199-206

    Article  CAS  PubMed  Google Scholar 

  • Sun D, Ding A (2006) MyD88-mediated stabilization of interferon-gamma-induced cytokine and chemokine mRNA. Nat Immunol 7: 375-381

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Takeda K, Takeuchi O, Tsujimura T, Itami S, Adachi O, Kawai T, Sanjo H, Yoshikawa K, Terada N, Akira S (1999) Limb and skin abnormalities in mice lacking IKKalpha. Science 284: 313-316

    Article  CAS  PubMed  Google Scholar 

  • Takeshita F, Ishii KJ, Kobiyama K, Kojima Y, Coban C, Sasaki S, Ishii N, Klinman DM, Okuda K, Akira S, Suzuki K (2005) TRAF4 acts as a silencer in TLR-mediated signaling through the association with TRAF6 and TRIF. Eur J Immunol 35: 2477-2485

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi O, Takeda K, Hoshino K, Adachi O, Ogawa T, Akira S (2000) Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol 12: 113-117

    Article  CAS  PubMed  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 Tolllike receptor 4. J Exp Med 195: 99-111

    Article  CAS  PubMed  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: 978-984

    CAS  PubMed  Google Scholar 

  • Traenckner EB, Pahl HL, Henkel T, Schmidt KN, Wilk S, Baeuerle PA (1995) Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. Embo J 14: 2876-2883

    CAS  PubMed  Google Scholar 

  • Trofimova M, Sprenkle AB, Green M, Sturgill TW, Goebl MG, Harrington MA (1996) Developmental and tissue-specific expression of mouse pelle-like protein kinase. J Biol Chem 271: 17609-17612

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Urdal DL, Call SM, Jackson JL, Dower SK (1988) Affinity purification and chemical analysis of the interleukin-1 receptor. J Biol Chem 263: 2870-2877

    CAS  PubMed  Google Scholar 

  • Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, Hacker H, Wagner H (2001) Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin1 receptor signaling pathway in innate immune cells. J Biol Chem 276: 31332-31339

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S (1995) Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 9: 2723-2735

    Article  CAS  PubMed  Google Scholar 

  • Vig E, Green M, Liu Y, Donner DB, Mukaida N, Goebl MG, Harrington MA (1999) Modulation of tumor necrosis factor and interleukin-1-dependent NF-kappaB activity by mPLK/IRAK. J Biol Chem 274: 13077-13084

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Weber AN, Moncrieffe MC, Gangloff M, Imler JL, Gay NJ (2005) Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway. J Biol Chem 280: 22793-22799

    Article  CAS  PubMed  Google Scholar 

  • Weber AN, Tauszig-Delamasure S, Hoffmann JA, Lelievre E, Gascan H, Ray KP, Morse MA, Imler JL, Gay NJ (2003) Binding of the Drosophila cytokine Spatzle to Toll is direct and establishes signaling. Natur Immunol 4: 794-800

    Article  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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Whiteside ST, Ernst MK, LeBail O, Laurent-Winter C, Rice N, Israel A (1995) N- and C-terminal sequences control degradation of MAD3/I kappa B alpha in response to inducers of NF-kappa B activity. Mol Cell Biol 15: 5339-5345

    CAS  PubMed  Google Scholar 

  • Wietek C, Miggin SM, Jefferies CA, O’Neill LA (2003) Interferon regulatory factor-3-mediated activation of the interferon-sensitive response element by Toll-like receptor (TLR) 4 but not TLR3 requires the p65 subunit of NF-kappa. J Biol Chem 278: 50923-50931

    Article  CAS  PubMed  Google Scholar 

  • Xu Y, Tao X, Shen B, Horng T, Medzhitov R, Manley JL, Tong L (2000) Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature 408: 111-115

    Article  CAS  PubMed  Google Scholar 

  • Yamagata M, Merlie JP, Sanes JR (1994) Interspecific comparisons reveal conserved features of the Drosophila Toll protein. Gene 139: 223-228

    Article  CAS  PubMed  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  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  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  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

    CAS  Google Scholar 

  • Yamamoto Y, Kim DW, Kwak YT, Prajapati S, Verma U, Gaynor RB (2001) IKKgamma/NEMO facilitates the recruitment of the IkappaB proteins into the IkappaB kinase complex. J Biol Chem 276: 36327-36336

    Article  CAS  PubMed  Google Scholar 

  • Yamaoka S, Courtois G, Bessia C, Whiteside ST, Weil R, Agou F, Kirk HE, Kay RJ, Israel A (1998) Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell 93: 1231-1240

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Zhang J, Xu LG, Han KJ, Wei X, Shu HB (2004) PIASy represses TRIF-induced ISRE and NFkappaB activation but not apoptosis. FEBS Lett 570: 97-101

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland

    Constantinos Brikos & Luke A. J. O’Neill

Authors
  1. Constantinos Brikos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luke A. J. O’Neill
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut für Immunologie BMFZ, Philipps-Universität Marburg, Hans-Meerwein-Str. 2, D-35043, Marburg, Germany

    Stefan Bauer

  2. Abteilung für Klinische Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, D-53105, Bonn, Germany

    Gunther Hartmann

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Brikos, C., O’Neill, L.A.J. (2008). Signalling of Toll-Like Receptors. In: Bauer, S., Hartmann, G. (eds) Toll-Like Receptors (TLRs) and Innate Immunity. Handbook of Experimental Pharmacology, vol 183. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-72167-3_2

Download citation

Publish with us

Policies and ethics

Search

Navigation