2d,h) To study the effect of Leishmania virulence on DC differen

2d,h). To study the effect of Leishmania virulence on DC differentiation, we tested the ability of the four Lm clones to interfere with the expression of CD1a, HLA-DR, CD80 and CD86 during DC differentiation. We observed that all tested Lm clones were able to down-modulate CD1a expression significantly when compared with DCs differentiated without parasites (P = 0·002) (Fig. 3). Epigenetics inhibitor No significant

differences were observed between HV and LV Lm clones. We also showed a slight decrease in HLA-DR and CD80 expression as well as a slight increase in CD86 expression in the presence of Lm promastigotes when compared to uninfected DCs, but these results were not significant (Fig. 3). To evaluate the impact of virulence on cytokine production by DCs, the

four Lm clones were incubated with immature DCs for 48 h and IL-12p70, IL-10 and TNF-α production was analysed. We did not observe significant differences in IL-12p70, IL-10 or TNF-α production between Lm-infected DCs and uninfected cells for all tested clones. The effect of virulence of Lm parasites was also analysed on cytokine production buy Kinase Inhibitor Library during IFN-γ-, LPS- or IFN-γ/LPS-induced maturation of DCs. As shown in Fig. 4, highly significant levels of IL-12p70, IL-10 and TNF-α were detected in infected and uninfected LPS or IFN-γ/LPS matured DCs when compared with immature cells. Interestingly, we observed that infected and LPS-matured DCs produced lower levels of IL-12p70 than uninfected LPS-matured DCs, whereas the presence of parasites did not affect IL-12p70 production in IFN-γ/LPS-matured DCs. No IL-12p70 production was detected in infected and IFN-γ-stimulated DCs. These results were observed regardless of Lm clones virulence. We also showed a slight increase of IL-10 production in the presence of all clones except LV and of

TNF-α production in the presence of HVΔlmpdi and LVΔlmpdi clones during LPS-induced maturation of DCs (Fig. 4). In this study, we evaluated correlations between human 3-oxoacyl-(acyl-carrier-protein) reductase DC response and Lm clones that were differentially pathogenic in BALB/c mice. The contrasting pathogenicity of these clones was more pronounced than it was for the isolates from which they were derived. Indeed, unlike the LV isolate that induced mild disease, the LV clone was not able to induce lesions in mice (unpublished data). We showed that infection rate and parasite burden were significantly higher in DCs infected with HV than with LV. Previously, using the wild Lm isolates LmHV and LmlV, we showed a significantly higher parasite burden in LmHV-infected human monocytes, suggesting that the high virulent isolate was able to replicate more rapidly inside the phagolysosome [23]. Here, we extend these observations to human DCs. We showed significant differences in uptake and intracellular growth of Lm clones having different levels of virulence. We also observed a significant decrease in infection rate and parasite burden in HVΔlmpdi-infected DCs compared with HV-infected DCs.

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