The biology of Toll-like receptors.

In 1997, a human homologue of the Drosophila Toll protein was described, a protein later to be designated Toll-like receptor 4 (TLR4). Since that time, additional human and murine TLR proteins have been identified. Mammalian TLR proteins appear to represent a conserved family of innate immune recognition receptors. These receptors are coupled to a signaling pathway that is conserved in mammals, insects, and plants, resulting in the activation of genes that mediate innate immune defenses. Numerous studies have now identified a wide variety of chemically-diverse bacterial products that serve as putative ligands for TLR proteins. More recent studies have identified the first endogenous protein ligands for TLR proteins. TLR signaling represents a key feature of innate immune response to pathogen invasion.

[1]  C. Janeway,et al.  The immune system evolved to discriminate infectious nonself from noninfectious self. , 1992, Immunology today.

[2]  S. Roth,et al.  The polarity of the dorsoventral axis in the drosophila embryo is defined by an extracellular signal , 1991, Cell.

[3]  S. Akira,et al.  The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5 , 2001, Nature.

[4]  Z. Cao,et al.  MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. , 1997, Immunity.

[5]  N. Qureshi,et al.  Diphosphoryl lipid A derived from lipopolysaccharide (LPS) of Rhodopseudomonas sphaeroides inhibits activation of 70Z/3 cells by LPS , 1991, Infection and immunity.

[6]  G. Stark,et al.  IRAK-M Is a Novel Member of the Pelle/Interleukin-1 Receptor-associated Kinase (IRAK) Family* , 1999, The Journal of Biological Chemistry.

[7]  C. Janeway,et al.  A human homologue of the Drosophila Toll protein signals activation of adaptive immunity , 1997, Nature.

[8]  Antony Rodriguez,et al.  The 18‐wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense , 1997, The EMBO journal.

[9]  A. Aderem,et al.  The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens , 1999, Nature.

[10]  Crafford A. Harris,et al.  Interleukin (IL)-1 Receptor–associated Kinase (IRAK) Requirement for Optimal Induction of Multiple IL-1 Signaling Pathways and IL-6 Production , 1998, The Journal of experimental medicine.

[11]  M. Meister,et al.  Insect immunity: the diptericin promoter contains multiple functional regulatory sequences homologous to mammalian acute-phase response elements. , 1993, Biochemical and biophysical research communications.

[12]  D. Golenbock,et al.  LPS‐binding proteins and receptors , 1998, Journal of leukocyte biology.

[13]  S. Akira,et al.  Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. , 1998, Immunity.

[14]  B. Lemaître,et al.  The Dorsoventral Regulatory Gene Cassette spätzle/Toll/cactus Controls the Potent Antifungal Response in Drosophila Adults , 1996, Cell.

[15]  B. Monks,et al.  Cutting edge: cells that carry A null allele for toll-like receptor 2 are capable of responding to endotoxin. , 1999, Journal of immunology.

[16]  L. Larivière,et al.  Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4) , 1999, The Journal of experimental medicine.

[17]  S. Wasserman,et al.  An activity-dependent network of interactions links the Rel protein Dorsal with its cytoplasmic regulators. , 1997, Development.

[18]  N. Gay,et al.  Drosophila Toll and IL-1 receptor , 1991, Nature.

[19]  C. Nüsslein-Volhard,et al.  cactus, a gene involved in dorsoventral pattern formation of Drosophila, is related to the IκB gene family of vertebrates , 1992, Cell.

[20]  A. Robidoux,et al.  E5531, a pure endotoxin antagonist of high potency. , 1995, Science.

[21]  T. Kirikae,et al.  Lipopolysaccharides (LPS) of Oral Black-Pigmented Bacteria Induce Tumor Necrosis Factor Production by LPS-Refractory C3H/HeJ Macrophages in a Way Different from That of Salmonella LPS , 1999, Infection and Immunity.

[22]  R. Ulevitch,et al.  CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. , 1990, Science.

[23]  S. Akira,et al.  Unresponsiveness of MyD88-deficient mice to endotoxin. , 1999, Immunity.

[24]  M. Gayle,et al.  T1/ST2 Signaling Establishes It as a Member of an Expanding Interleukin-1 Receptor Family (*) , 1996, The Journal of Biological Chemistry.

[25]  C. Janeway,et al.  ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. , 1999, Genes & development.

[26]  D. Golenbock,et al.  Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. , 1999, Journal of immunology.

[27]  K. Tanamoto,et al.  The lipid A moiety of Porphyromonas gingivalis lipopolysaccharide specifically mediates the activation of C3H/HeJ mice. , 1997, Journal of immunology.

[28]  H. Kolb,et al.  Cutting Edge: Heat Shock Protein 60 Is a Putative Endogenous Ligand of the Toll-Like Receptor-4 Complex1 , 2000, The Journal of Immunology.

[29]  Michael Karin,et al.  The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[30]  B. Monks,et al.  Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. , 2000, The Journal of clinical investigation.

[31]  R. Delotto,et al.  Proteolytic processing of the Drosophila Spätzle protein by Easter generates a dimeric NGF-like molecule with ventralising activity , 1998, Mechanisms of Development.

[32]  G. Salvesen,et al.  The Regulation of Anoikis: MEKK-1 Activation Requires Cleavage by Caspases , 1997, Cell.

[33]  B. Trask,et al.  Cloning and characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in humans. , 1998, Blood.

[34]  T. Mayadas,et al.  Use of a photoactivatable taxol analogue to identify unique cellular targets in murine macrophages: identification of murine CD18 as a major taxol-binding protein and a role for Mac-1 in taxol-induced gene expression. , 1999, Journal of immunology.

[35]  J. Botas,et al.  The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll. , 1994, Development.

[36]  Sung-jun Han,et al.  Lipopolysaccharide-activated Kinase, an Essential Component for the Induction of the Antimicrobial Peptide Genes inDrosophila melanogaster Cells* , 2000, The Journal of Biological Chemistry.

[37]  P. Godowski,et al.  Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. , 1999, Science.

[38]  C. Janeway,et al.  Innate Immunity: The Virtues of a Nonclonal System of Recognition , 1997, Cell.

[39]  B. Beutler,et al.  Diphosphoryl lipid A from Rhodopseudomonas sphaeroides ATCC 17023 blocks induction of cachectin in macrophages by lipopolysaccharide , 1989, Infection and immunity.

[40]  Jerome F. Strauss,et al.  The Extra Domain A of Fibronectin Activates Toll-like Receptor 4* , 2001, The Journal of Biological Chemistry.

[41]  D. Golenbock,et al.  Toll-like Receptor 2 Functions as a Pattern Recognition Receptor for Diverse Bacterial Products* , 1999, The Journal of Biological Chemistry.

[42]  K. Anderson,et al.  The Toll gene of drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein , 1988, Cell.

[43]  A. Gurney,et al.  Signaling events induced by lipopolysaccharide-activated toll-like receptor 2. , 1999, Journal of immunology.

[44]  P. Feng,et al.  IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. , 1997, Science.

[45]  D. Golenbock,et al.  The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. , 1999, Journal of immunology.

[46]  S. Akira,et al.  TLR6: A novel member of an expanding toll-like receptor family. , 1999, Gene.

[47]  D. Rosenstreich,et al.  BCG-induced enhancement of endotoxin sensitivity in C3H/HeJ mice. I. In vivo studies. , 1980, Journal of immunology.

[48]  S. Saccani,et al.  The Human Toll Signaling Pathway: Divergence of Nuclear Factor κB and JNK/SAPK Activation Upstream of Tumor Necrosis Factor Receptor–associated Factor 6 (TRAF6) , 1998, The Journal of experimental medicine.

[49]  J. Silver,et al.  Resistance to endotoxin shock and reduced dissemination of gram-negative bacteria in CD14-deficient mice. , 1996, Immunity.

[50]  S. Morony,et al.  TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. , 1999, Genes & development.

[51]  K. Anderson,et al.  The spätzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo , 1994, Cell.

[52]  P. Georgel,et al.  Drosophila immunity: a comparative analysis of the Rel proteins dorsal and Dif in the induction of the genes encoding diptericin and cecropin. , 1996, Nucleic acids research.

[53]  Z. Cao,et al.  IRAK: A Kinase Associated with the Interleukin-1 Receptor , 1996, Science.

[54]  L. O’Neill,et al.  Signal transduction pathways activated by the IL‐1 receptor family: ancient signaling machinery in mammals, insects, and plants , 1998, Journal of leukocyte biology.

[55]  A. Aderem,et al.  Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[56]  Yoshinori Nagai,et al.  MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4 , 1999, The Journal of experimental medicine.

[57]  R. Thieringer,et al.  CD14 enhances cellular responses to endotoxin without imparting ligand-specific recognition. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[58]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[59]  R. M. Wooten,et al.  Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. , 1999, Journal of immunology.

[60]  M. Fenton,et al.  Roles of lipoarabinomannan in the pathogenesis of tuberculosis. , 1999, Microbes and infection.

[61]  C. Nathan,et al.  Shared actions of endotoxin and taxol on TNF receptors and TNF release. , 1990, Science.

[62]  S. Wasserman,et al.  Impaired cytokine signaling in mice lacking the IL-1 receptor-associated kinase. , 1999, Journal of immunology.

[63]  S. Akira,et al.  Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. , 1999, Immunity.

[64]  A. Gurney,et al.  Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling , 1998, Nature.

[65]  D. Golenbock,et al.  Mycobacterial lipoarabinomannan recognition requires a receptor that shares components of the endotoxin signaling system. , 1996, Journal of immunology.

[66]  S. Akira,et al.  IKK-i, a novel lipopolysaccharide-inducible kinase that is related to IkappaB kinases. , 1999, International immunology.

[67]  M. Rothe,et al.  Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2* , 1999, The Journal of Biological Chemistry.

[68]  A. Aderem,et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[69]  G. Hardiman,et al.  A family of human receptors structurally related to Drosophila Toll. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[70]  T. Yoshida,et al.  Mouse Toll-like Receptor 4·MD-2 Complex Mediates Lipopolysaccharide-mimetic Signal Transduction by Taxol* , 2000, The Journal of Biological Chemistry.

[71]  M. Rothe,et al.  Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide , 1998, The Journal of experimental medicine.

[72]  B. Bloom,et al.  Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. , 1999, Science.

[73]  S. Akira,et al.  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 Pathway1 , 2000, The Journal of Immunology.

[74]  F. Gusovsky,et al.  Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction* , 1999, The Journal of Biological Chemistry.

[75]  C. Janeway,et al.  MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. , 1998, Molecular cell.

[76]  S. Kidd Characterization of the Drosophila cactus locus and analysis of interactions between cactus and dorsal proteins , 1992, Cell.

[77]  Zhaodan Cao,et al.  TRAF6 is a signal transducer for interleukin-1 , 1996, Nature.

[78]  D. Golenbock,et al.  Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. , 1991, The Journal of biological chemistry.

[79]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[80]  P. Scheurich,et al.  TNF receptor associated factors in cytokine signaling. , 1999, Cytokine & growth factor reviews.

[81]  K. Anderson,et al.  Regulated nuclear import of Rel proteins in the Drosophila immune response , 1998, Nature.

[82]  L. Larivière,et al.  Cutting edge: functional characterization of the effect of the C3H/HeJ defect in mice that lack an Lpsn gene: in vivo evidence for a dominant negative mutation. , 1999, Journal of immunology.