Co-operative Induction of Pro-Inflammatory Signaling by Toll-like Receptors

J Endotoxin Res. 2000;6(5):393-6.

Abstract

Toll-like receptors (TLRs) mediate detection of a broad range of pathogens and pathogen-derived products including LPS, peptidoglycan, bacterial lipopeptides, and lipoteichoic acid. Recent evidence indicates that the broad specificity of TLRs may be a consequence of the interactions between different TLRs. In this report, we demonstrate that while a constitutively active TLR4 homodimer can induce the production of pro-inflammatory cytokines, homodimers of TLR2 and TLR6 cannot. However, when co-expressed in the same cell, constitutively active TLR2 and TLR6 strongly induce cytokine production, indicating that these TLRs require partners to productively signal. Since TLR4 signals as a homodimer, while TLR2 and TLR6 do not, it is clear that, despite the conservation of their cytoplasmic signaling domains, the mechanisms by which they initiate signaling are different. We have localized the region of TLR4 that mediates its ability to signal as a homodimer to the membrane-proximal half of the cytoplasmic tail of the receptor.

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Dimerization
  • Drosophila Proteins*
  • Inflammation Mediators / chemistry
  • Inflammation Mediators / immunology*
  • Luciferases / genetics
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Signal Transduction
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Transfection

Substances

  • Drosophila Proteins
  • Inflammation Mediators
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Luciferases