Toll receptors in innate immunity.

Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to infectious agents. In addition, the cells and molecules operating during this early stage of the immune response in vertebrates have a decisive impact on the shaping of the subsequent adaptive response. Genetic studies initially performed in the fruitfly Drosophila and later in mice have revealed the importance of proteins of the Toll family in the innate immune response. We present here our current understanding of the role of this evolutionary ancient family of proteins that are thought to function as cytokine receptors (Toll in Drosophila) or pattern-recognition receptors (TLRs in mammals) and activate similar, albeit non-identical, signal-transduction pathways in flies and mammals.

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

[2]  T. Serikawa,et al.  Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase , 1999, Nature Genetics.

[3]  K. Anderson,et al.  The antibacterial arm of the drosophila innate immune response requires an IkappaB kinase. , 2001, Genes & development.

[4]  S. Sprang,et al.  Three-Dimensional Structure of a Complex between the Death Domains of Pelle and Tube , 1999, Cell.

[5]  A. Aderem,et al.  Cutting Edge: Functional Interactions Between Toll-Like Receptor (TLR) 2 and TLR1 or TLR6 in Response to Phenol-Soluble Modulin1 , 2001, The Journal of Immunology.

[6]  P. Ricciardi-Castagnoli,et al.  Physical contact between lipopolysaccharide and toll-like receptor 4 revealed by genetic complementation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[8]  Robert Geisler,et al.  A gradient of cytoplasmic Cactus degradation establishes the nuclear localization gradient of the dorsal morphogen in Drosophila , 1996, Mechanisms of Development.

[9]  J. Hoffmann,et al.  The Rel protein DIF mediates the antifungal but not the antibacterial host defense in Drosophila. , 2000, Immunity.

[10]  P. Godowski,et al.  The apoptotic signaling pathway activated by Toll‐like receptor‐2 , 2000, The EMBO journal.

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

[12]  R. Ulevitch,et al.  Recognition of gram-negative bacteria and endotoxin by the innate immune system. , 1999, Current opinion in immunology.

[13]  P. Allavena,et al.  Differential Expression and Regulation of Toll-Like Receptors (TLR) in Human Leukocytes: Selective Expression of TLR3 in Dendritic Cells1 , 2000, The Journal of Immunology.

[14]  K. Mizuguchi,et al.  Getting knotted: a model for the structure and activation of Spätzle. , 1998, Trends in biochemical sciences.

[15]  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.

[16]  K. Miyake,et al.  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 Components1 , 2001, The Journal of Immunology.

[17]  R. Steward,et al.  A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF , 1999, The EMBO journal.

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

[19]  P. Godowski,et al.  Microbial Lipopeptides Stimulate Dendritic Cell Maturation Via Toll-Like Receptor 21 , 2001, The Journal of Immunology.

[20]  M. Elrod-Erickson,et al.  Interactions between the cellular and humoral immune responses in Drosophila , 2000, Current Biology.

[21]  S. Akira,et al.  [Induction of direct antimicrobial activity through mammalian toll-like receptors]. , 2001, Pneumologie.

[22]  A. Medvedev,et al.  Bacterial Lipopolysaccharide and IFN-γ Induce Toll-Like Receptor 2 and Toll-Like Receptor 4 Expression in Human Endothelial Cells: Role of NF-κB Activation1 , 2001, The Journal of Immunology.

[23]  D. Golenbock,et al.  The biology of Toll-like receptors. , 2000, Cytokine & growth factor reviews.

[24]  M. Meister,et al.  A recessive mutation, immune deficiency (imd), defines two distinct control pathways in the Drosophila host defense. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  A. Israël The IKK complex: an integrator of all signals that activate NF-κB? , 2000 .

[26]  P. Godowski,et al.  Toll-like receptor 2–mediated NF-κB activation requires a Rac1-dependent pathway , 2000, Nature Immunology.

[27]  Y. Ip,et al.  Toll receptor-mediated Drosophila immune response requires Dif, an NF-κB factor , 1999 .

[28]  S. Akira,et al.  Expression of Toll-Like Receptor 2 on γδ T Cells Bearing Invariant Vγ6/Vδ1 Induced by Escherichia coli Infection in Mice1 , 2000, The Journal of Immunology.

[29]  A. Hoffmann,et al.  Nucleosome remodeling at the IL-12 p40 promoter is a TLR-dependent, Rel-independent event , 2001, Nature Immunology.

[30]  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.

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

[32]  K. Anderson,et al.  A conserved signaling pathway: the Drosophila toll-dorsal pathway. , 1996, Annual review of cell and developmental biology.

[33]  F C Kafatos,et al.  Phylogenetic perspectives in innate immunity. , 1999, Science.

[34]  D. Podolsky,et al.  Lipopolysaccharide Activates Distinct Signaling Pathways in Intestinal Epithelial Cell Lines Expressing Toll-Like Receptors1 , 2000, The Journal of Immunology.

[35]  N. Gay,et al.  The Drosophila membrane receptor Toll can function to promote cellular adhesion. , 1990, The EMBO journal.

[36]  Y. Engström Induction and regulation of antimicrobial peptides in Drosophila. , 1999, Developmental and comparative immunology.

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

[38]  J. Hoffmann,et al.  Signaling mechanisms in the antimicrobial host defense of Drosophila. , 2000, Current opinion in microbiology.

[39]  B. Beutler,et al.  Three novel mammalian toll-like receptors: gene structure, expression, and evolution. , 2000, European cytokine network.

[40]  S. Dower,et al.  Regulation of Toll-Like Receptors in Human Monocytes and Dendritic Cells1 , 2001, The Journal of Immunology.

[41]  M. Ashburner,et al.  Constitutive activation of toll-mediated antifungal defense in serpin-deficient Drosophila. , 1999, Science.

[42]  I. Andó,et al.  Relish, a central factor in the control of humoral but not cellular immunity in Drosophila. , 1999, Molecular cell.

[43]  R. Medzhitov,et al.  The Toll-receptor family and control of innate immunity. , 1999, Current opinion in immunology.

[44]  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.

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

[46]  B. Thomma,et al.  The complexity of disease signaling in Arabidopsis. , 2001, Current opinion in immunology.

[47]  G. Martin,et al.  Innate immunity in plants. , 2001, Current opinion in immunology.

[48]  S. Randell,et al.  CD14-dependent Lipopolysaccharide-induced β-Defensin-2 Expression in Human Tracheobronchial Epithelium* , 2000, The Journal of Biological Chemistry.

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

[50]  Zhijian J. Chen,et al.  Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain , 2000, Cell.

[51]  S. Dinesh-Kumar,et al.  Structure-function analysis of the tobacco mosaic virus resistance gene N. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[52]  Antony Rodriguez,et al.  The Drosophila caspase Dredd is required to resist Gram‐negative bacterial infection , 2000, EMBO reports.

[53]  R. Steward,et al.  Cactus-independent regulation of Dorsal nuclear import by the ventral signal , 2000, Current Biology.

[54]  B. Lemaître,et al.  Genes that fight infection: what the Drosophila genome says about animal immunity. , 2000, Trends in genetics : TIG.

[55]  L. Tong,et al.  Structural basis for signal transduction by the Toll/interleukin-1 receptor domains , 2000, Nature.

[56]  C. Janeway Approaching the asymptote? Evolution and revolution in immunology. , 1989, Cold Spring Harbor symposia on quantitative biology.

[57]  B. Ponder,et al.  Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. , 1999, Molecular cell.

[58]  J. Hoffmann,et al.  Innate immunity in higher insects. , 1996, Current opinion in immunology.

[59]  J. Manley,et al.  Phosphorylation modulates direct interactions between the Toll receptor, Pelle kinase and Tube. , 1998, Development.

[60]  S. Wasserman,et al.  Toll signaling: the enigma variations. , 2000, Current opinion in genetics & development.

[61]  R. Zhou,et al.  Role of Drosophila IKKγ in a Toll-independent antibacterial immune response , 2000, Nature Immunology.

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

[63]  G. Nemerow,et al.  MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  K. Rajewsky,et al.  The Toll-like Receptor Protein Rp105 Regulates Lipopolysaccharide Signaling in B Cells , 2000, The Journal of experimental medicine.

[65]  Istvan Ando,et al.  Activation of the Drosophila NF‐κB factor Relish by rapid endoproteolytic cleavage , 2000, EMBO reports.

[66]  J. Hoffmann,et al.  Toll-related receptors and the control of antimicrobial peptide expression in Drosophila. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

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

[68]  E. Kiss-Toth,et al.  Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses1 , 2000, The Journal of Immunology.

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

[70]  T. Maniatis,et al.  A Drosophila IkappaB kinase complex required for Relish cleavage and antibacterial immunity. , 2000, Genes & development.

[71]  K. Takeda,et al.  Cutting Edge: Cell Surface Expression and Lipopolysaccharide Signaling Via the Toll-Like Receptor 4-MD-2 Complex on Mouse Peritoneal Macrophages1 , 2000, The Journal of Immunology.