The gut is home to a large number of Treg, with both CD4(+) CD25(+) Treg and bacterial antigen-specific Tr1 cells present in normal mouse intestinal lamina propria. It has been shown recently that intestinal mucosal DC are able to induce Foxp3(+) Treg through production of TGF-beta plus retinoic acid (RA). However, the factors instructing DC toward this mucosal phenotype are currently unknown. Curcumin has been shown to possess a number of biologic activities including the inhibition of NF-kappaB signaling. We asked whether curcumin could modulate DC to be tolerogenic whose function could mimic mucosal DC. We report here that curcumin modulated BM-derived DC to express ALDH1a and IL-10. These curcumin-treated DC induced differentiation of naïve CD4(+) T cells into Treg resembling Treg in the intestine, including both CD4(+)CD25(+) Foxp3(+) Treg and IL-10-producing Tr1 cells. Such Treg induction required IL-10, TGF-beta and retinoic acid produced by curcumin-modulated DC. Cell contact as well as IL-10 and TGF-beta production were involved in the function of such induced Treg. More importantly, these Treg inhibited antigen-specific T-cell activation in vitro and inhibited colitis due to antigen-specific pathogenic T cells in vivo.