Differential Effects of CpG-DNA in Toll-like receptor-2/-4/-9 Tolerance and Cross-Tolerance

Immunology. 2005 Oct;116(2):203-12. doi: 10.1111/j.1365-2567.2005.02211.x.


Lipopolysaccharide (LPS) tolerance is a state of refractoriness towards a second stimulation by LPS after a preceding stimulation. LPS is recognized by Toll-like receptor-4 (TLR-4), which belongs to a group of pattern recognition receptors mediating activation of innate immunity by microbial components. To date, it is not known in detail to what extent other TLR-dependent stimuli also induce tolerance and whether preceding and challenging stimuli are interchangeable. We have examined tolerance induction in detail for lipoteichoic acid (LTA), LPS and CpG-DNA, which are recognized by TLR-2, -4 and -9, respectively. In RAW264.7 macrophages, all three stimuli induced tolerance towards a subsequent challenge with the same stimulus used for priming, as well as cross-tolerance towards subsequent challenge with other stimuli signalling via different TLRs. However, whereas LPS/LTA cross-tolerance was also functional in an in vivo model of galactosamine (GalN)-primed liver damage, pretreatment with CpG only protected against GalN/CpG challenge and failed to induce cross-tolerance for LPS and LTA. CpG-DNA pretreatment even enhanced tumour necrosis factor (TNF)-alpha production and liver damage upon subsequent challenge with LPS or LTA. Stimulation with CpG-DNA resulted in a peculiar sensitization for interferon (IFN)-gamma secretion. The data indicate that, in contrast to in vitro macrophage desensitization, the in vivo consequences of repeated TLR stimulation greatly differ amongst different TLR ligands.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / immunology
  • CpG Islands
  • DNA-Binding Proteins / immunology
  • Immune Tolerance*
  • Interferon-gamma / biosynthesis
  • Interleukin-18 / biosynthesis
  • Interleukin-18 / immunology
  • Ligands
  • Lipopolysaccharides / immunology
  • Macrophages, Peritoneal / immunology
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Inbred Strains
  • Oligodeoxyribonucleotides / immunology*
  • Receptors, Cell Surface / immunology*
  • Receptors, Immunologic / immunology
  • Teichoic Acids / immunology
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Toll-Like Receptors


  • CPG-oligonucleotide
  • DNA-Binding Proteins
  • Interleukin-18
  • Ligands
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Teichoic Acids
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Toll-Like Receptors
  • lipoteichoic acid
  • Interferon-gamma