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^hiCD127^loforkhead 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_regsin vitro and in vivo.