Abstract
Stimulation of naive mouse dendritic cells (DC) with LPS or Pam(3)CSK(4) (P3C) induces production of TNF-alpha via TLR4- or TLR2-signaling. Although tolerance in macrophages has been studied in detail, we investigated the role of TLR agonist concentration and IL-6 for tolerance in DC. P3C- or LPS-primed DC were nonresponsive to P3C or LPS restimulation in terms of TNF-alpha but not IL-6 production. The mechanisms involved in tolerance were dependent on the concentration of the TLR ligand used for DC priming. DC primed with LPS or P3C at high concentrations developed a maturation dependent, IL-6 independent tolerance associated with inhibition of TLR signaling upstream of IkappaB as indicated by decreased IkappaB degradation. In contrast, priming of DC with LPS or P3C at low concentrations resulted in IL-6-dependent tolerance, which was abolished in IL-6 deficient DC, and was not accompanied by maturation of DC or by down-regulation of TLR2 or TLR4. In homotolerogenic DC primed with LPS or P3C at high concentrations, degradation of IkappaB upon restimulation with LPS or P3C was inhibited suggesting tolerance mechanism(s) upstream of IkappaB; in contrast, cross-tolerance in DC primed with LPS or P3C at low concentrations was not associated with reduced IkappaB degradation suggesting tolerance mechanisms downstream of IkappaB. Our data indicate that in naive DC TLR4- and TLR2-stimulation results in homo- and cross-tolerance; the mechanisms involved in tolerance depend on the concentration of the TLR agonist used for DC priming and are governed by IL-6 and maturation.
Highlights
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Priming of dendritic cells (DC) with LPS resulted in a significantly decreased production of TNF-␣ upon restimulation with LPS or P3C. This nonresponsiveness was designated as homo(LPS restimulation) or cross- (P3C restimulation) tolerance (Fig. 2A); comparable findings were obtained upon priming of DC at high concentrations of P3C (Fig. 2B). These results suggest that high concentrations of TLR2 or TLR4 agonists induce both LPS/ P3C homo- and LPS/P3C cross-tolerant DC designated as LPShigh and P3Chigh tolerance, respectively
We examined the effect of priming DC with a bacterial cell wall component or a lipopeptide analog that are both recognized by distinct TLRs on their state of tolerance toward subsequent restimulation
Summary
Our data indicate that in naive DC TLR4- and TLR2-stimulation results in homo- and cross-tolerance; the mechanisms involved in tolerance depend on the concentration of the TLR agonist used for DC priming and are governed by IL-6 and maturation. Priming with LPS or P3C at low concentrations induces cross- and homo-tolerant DC dependent on IL-6 but independent of maturation
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