Present address: Inflammation Pharmacology, ALTANA Pharma AG, 78467 Konstanz, Germany.
Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance
Article first published online: 13 SEP 2005
Volume 116, Issue 2, pages 203–212, October 2005
How to Cite
Dalpke, A. H., Lehner, M. D., Hartung, T. and Heeg, K. (2005), Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance. Immunology, 116: 203–212. doi: 10.1111/j.1365-2567.2005.02211.x
- Issue published online: 13 SEP 2005
- Article first published online: 13 SEP 2005
- Received 13 December 2004; revised 5 April 2005; accepted 10 May 2005.
- lipoteichoic acid;
- Toll-like receptors
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)-α production and liver damage upon subsequent challenge with LPS or LTA. Stimulation with CpG-DNA resulted in a peculiar sensitization for interferon (IFN)-γ 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.