Curcumin induces maturation-arrested dendritic cells that expand regulatory T cells in vitro and in vivo

P>Dendritic cells (DC) and regulatory T cells (T-regs) are vital to the development of transplant tolerance. Curcumin is a novel biological agent extracted from Curcuma longa (turmeric), with anti-inflammatory and anti-oxidant activity mediated via nuclear factor (NF)-kappa B inhibition. We investigated the immunomodulatory effects of curcumin on human monocyte-derived and murine DC. Human monocyte-derived DC (hu-Mo-DC) were generated in the presence (CurcDC) or absence (matDC) of 25 mu M curcumin, and matured using lipopolysaccharide (1 mu g/ml). DC phenotype and allostimulatory capacity was assessed. CD11c+ DC were isolated from C57BL/6 mice, pretreated with curcumin and injected into BALB/c mice, followed by evaluation of in vivo T cell populations and alloproliferative response. Curcumin induced DC differentiation towards maturation-arrest. CurcDC demonstrated minimal CD83 expression (< 2%), down-regulation of CD80 and CD86 (50% and 30%, respectively) and reduction (10%) in both major histocompatibility complex (MHC) class II and CD40 expression compared to matDC. CurcDC also displayed decreased RelB and interleukin (IL)-12 mRNA and protein expression. Functionally, CurcDC allostimulatory capacity was decreased by up to 60% (P < 0 center dot 001) and intracellular interferon (IFN-gamma) expression in the responding T cell population were reduced by 50% (P < 0 center dot 05). T cell hyporesponsiveness was due to generation of CD4+CD25hiCD127loforkhead box P3 (FoxP3)+ T-regs that exerted suppressive functions on naive syngeneic T cells, although the effect was not antigen-specific. In mice, in vivo infusion of allogeneic CurcDC promoted development of FoxP3+ T-regs and reduced subsequent alloproliferative capacity. Curcumin arrests maturation of DC and induces a tolerogenic phenotype that subsequently promotes functional FoxP3+ T(regs)in vitro and in vivo.