Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro, and exhibits protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-B. While it has been demonstrated effective in reducing relapse rate in ulcerative colitis patients, curcumin's effectiveness in Crohn's disease (CD) or in Th-1/Th-17 mediated immune models of CD has not been evaluated. Therefore, we investigated the effects of dietary curcumin (0.1-1%) on the development of colitis, immune activation and in vivo NF-B activity in germ-free IL-10^-/- or IL-10^-/-;NF-B^EGFP mice colonized with specific pathogen-free microflora. Proximal and distal colon morphology showed a mild protective effect of curcumin only at 0.1%. Colonic IFN- and IL-12/23p40 mRNA expression followed similar pattern (~50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN- by colonic explants and mesenteric lymph node cells was elevated in IL-10^-/- mice, and was not decreased by dietary curcumin. Surprisingly, activation of NF-B in IL-10^-/- mice (phospho-NF-Bp65) or in IL-10^-/-;NF-B^EGFP mice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to down-regulate NF-B activity in IEC and IL-12/23p40 production by splenocytes and dendritic cells. In conclusion, curcumin demonstrates limited effectiveness on Th-1 mediated colitis in IL-10^-/- mice, with moderately improved colonic morphology, but with no significant effect on pathogenic T cell responses and in situ NF-B activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent.