Limited effects of dietary curcumin on Th-1 driven colitis in IL-10 deficient mice suggest an IL-10-dependent mechanism of protection.
Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro and exhibits a protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-kappaB. Although 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-kappaB activity in germ-free IL-10(-/-) or IL-10(-/-);NF-kappaB(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-gamma and IL-12/23p40 mRNA expression followed similar pattern ( approximately 50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN-gamma 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-kappaB in IL-10(-/-) mice (phospho-NF-kappaBp65) or in IL-10(-/-);NF-kappaB(EGFP) mice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to downregulate NF-kappaB 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-kappaB activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent.
Larmonier
C B
CB
Dept. of Pediatrics, Steele Children's Research Center, Univ. of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
Uno
J K
JK
Lee
Kang-Moon
KM
Karrasch
T
T
Laubitz
D
D
Thurston
R
R
Midura-Kiela
M T
MT
Ghishan
F K
FK
Sartor
R B
RB
Jobin
C
C
Kiela
P R
PR
D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000187:drug effects / Q000502:physiology*
D016328:NF-kappa B; D016753:Interleukin-10; D003474:Curcumin