文摘
Purpose
Dendritic cells (DCs) play a central role in regulating immune responses and govern T cell priming and polarization, mediating immunity and tolerance. Recent progress uncovered canonical Wnt signaling pathway as a novel maturation pathway that achieves DC tolerance induction without inflammatory cytokines. In this study, we investigated the effect of dexamethasone (Dex) on ¦Â-catenin-dependent pathway and IFN-¦Ã production for inducing tolerogenic DCs. Method: Human peripheral blood CD14+ monocytes were cultured for 6 days with granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-4 (immature DC (iDC)) and then pretreatment with or without Dex for 2 h and then treated with LPS (mature DC (mDC)) for 24 h. Immunophenotypic characterizations of DCs were analysed by flow cytometry. The supernatants were collected and cytokines [IL-12p70, IL-10, tumor necrosis factor-alpha (TNF-¦Á), interferon-gamma (IFN-¦Ã)] were assessed. The proteins were extracted and incubated with antibodies against the total or phosphorylated forms of ¦Â-catenin, GSK-3¦Â, and MAPKs. Results: Our results showed that the Dex blocked the terminal maturation of already differentiated DCs. Dex down-regulated the expression of CD86, CD40, CD83, CD80 and HLA-DR on DCs and inhibit IL-12p70, TNF-¦Á, especially IFN-¦Ã but increased levels of IL-10 production by DCs following LPS stimulation. Consequently, these Dex-DCs have a low stimulatory effect on allogeneic T cells and a reduced capacity to induce Th1 responses by naive T cells. Pretreatment with Dex significantly increased the non-phosphorylated of ¦Â-catenin but inhibited the phosphorylated of GSK-3¦Â. Inhibition of ¦Â-catenin enhanced IFN-¦Ã production along with Th1 responses by DCs stimulated with Dex but did not affect other cytokines production. The activation of ¦Â-catenin is not dependent on inhibition of GSK-3¦Â. However, we found that MAPK pathways changes could account for the activation of ¦Â-catenin by Dex. Conclusion: Our results suggest that Dex-induced tolerogenic DCs involvement in activating the ¦Â-catenin-dependent pathway. The strong immunosuppressive effect on decreased secretion of IFN-¦Ã is therefore accompanied by a shift in T cell balance.
