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

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)-κB 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 µM curcumin, and matured using lipopolysaccharide (1 µg/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 < 0·001) and intracellular interferon (IFN-γ) expression in the responding T cell population were reduced by 50% (P < 0·05). T cell hyporesponsiveness was due to generation of CD4(+) CD25(hi) CD127(lo) forkhead box P3 (FoxP3)(+) T(regs) that exerted suppressive functions on naïve 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.