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Toll-Like Receptors in the Mammalian Innate Immune System

  • Andrei E. Medvedev
  • Stefanie N. Vogel
Part of the Nucleic Acids and Molecular Biology book series (NUCLEIC, volume 21)

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.

Keywords

TLR4 Polymorphism Asp299Gly Polymorphism Downstream Adapter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • Andrei E. Medvedev
    • 1
  • Stefanie N. Vogel
    • 1
  1. 1.Department of Microbiology and Immunology, School of MedicineUniversity of Maryland, Baltimore (UMB)BaltimoreUSA

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