Protective effects of dietary curcumin in mouse model of chemically induced colitis are strain dependent:

Curcumin (diferulolylmethane) has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. Trinitrobenzene sulfonic acid (TNBS) colitis in NKT-deficient SJL/J mice has been described as Th1-mediated inflammation, whereas BALB/c mice are believed to exhibit a mixed Th1/Th2 response

Novel therapeutic strategy for the treatment of Inflammatory Bowel Diseases

At least 1.4 million of Americans suffer from Inflammatory Bowel Diseases (IBD). IBD (Crohn’s disease and ulcerative colitis) is a spontaneously relapsing, immunologically mediated disorder of the gastrointestinal tract. Complete medical cure remains a challenge and the probability of relapse is over 70%. Curcumin has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. The objective of this research project was to provide a preclinical evaluation of curcumin’s efficacy in relevant models of human IBD, and to investigate the molecular mechanisms of its protective mechanism of action. (1) We investigated the effect of dietary curcumin in trinitrobenzene sulfonic acid (TNBS)-induced colitis in SJL/J mice (Th-1/Th-17 response) and in BALB/c mice (Th-1/Th-2 response). We demonstrated that the efficacy of dietary curcumin varies in the two strains. Although the exact mechanism underlying these differences remains unclear, our observations suggest that the therapeutic value of dietary curcumin may vary depending on the nature of immune dysregulation. (2) We further confirmed those findings and we investigated the effects of curcumin on the development of colitis, immune activation, and in vivo NF-κB activity in germ-free IL-10^(–/–) colonized with specific pathogen-free microflora. In this model resembling CD, we demonstrated that IL-10 and curcumin act synergistically to downregulate inflammation. (3) Neutrophil aberrant accumulation at the intestinal mucosa is a characteristic hallmark of inflammatory conditions such as ulcerative colitis. Neutrophil transepithelial migration leads to an impaired epithelial barrier function, perpetuation of inflammation and tissue destruction. Therefore, we investigated the effect of curcumin on neutrophil polarization and motility. Our results indicated that curcumin interferes with colonic inflammation partly through chemokine expression inhibition and neutrophil chemotaxis and chemokinesis inhibition. We also demonstrated that curcumin significantly reduced epithelial tissue injury generated by neutrophil transepithelial migration and protease release. Those findings significantly add to our understanding of the mechanism by which curcumin affects the innate and adaptive immune response in IBD and may help develop innovative therapeutic strategy for IBD

Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL− Tumors

Abstract Imatinib mesylate (Gleevec, STI571), a selective inhibitor of a restricted number of tyrosine kinases, has been effectively used for the treatment of Philadelphia chromosome-positive leukemias and gastrointestinal stromal tumors. Imatinib may also directly influence immune cells. Suppressive as well as stimulating effects of this drug on CD4+ and CD8+ T lymphocytes or dendritic cells have been reported. In the current study, we have investigated the influence of imatinib mesylate on CD4+CD25+FoxP3+ regulatory T cells (Treg), a critical population of lymphocytes that contributes to peripheral tolerance. Used at concentrations achieved clinically, imatinib impaired Treg immunosuppressive function and FoxP3 expression but not production of IL-10 and TGF-β in vitro. Imatinib significantly reduced the activation of the transcription factors STAT3 and STAT5 in Treg. Analysis of Treg TCR-induced signaling cascade indicated that imatinib inhibited phosphorylation of ZAP70 and LAT. Substantiating these observations, imatinib treatment of mice decreased Treg frequency and impaired their immunosuppressive function in vivo. Furthermore, imatinib mesylate significantly enhanced antitumor immune responses to dendritic cell-based immunization against an imatinib-resistant BCR-ABL negative lymphoma. The clinical applications of imatinib mesylate might thus be expanded with its use as a potent immunomodulatory agent targeting Treg in cancer immunotherapy.</jats:p

Protective effects of dietary curcumin in mouse model of chemically induced colitis are strain dependent

BACKGROUND: Curcumin (diferulolylmethane) has been shown to have a protective role in mouse models of inflammatory bowel diseases (IBD) and to reduce the relapse rate in human ulcerative colitis (UC), thus making it a potentially viable supportive treatment option. Trinitrobenzene sulfonic acid (TNBS) colitis in NKT-deficient SJL/J mice has been described as Th1-mediated inflammation, whereas BALB/c mice are believed to exhibit a mixed Th1/Th2 response. METHODS: We therefore investigated the effect of dietary curcumin in colitis induced in these 2 strains. RESULTS: In the BALB/c mice, curcumin significantly increased survival, prevented weight loss, and normalized disease activity. In the SJL/J mice, curcumin demonstrated no protective effects. Genomewide microarray analysis of colonic gene expression was employed to define the differential effect of curcumin in these 2 strains. This analysis not only confirmed the disparate responses of the 2 strains to curcumin but also indicated different responses to TNBS. Curcumin inhibited proliferation of splenocytes from naive BALB/c mice but not SJL/J mice when nonspecifically stimulated in vitro with concanavalin A (ConA). Proliferation of CD4(+) splenocytes was inhibited in both strains, albeit with about a 2-fold higher IC(50) in SJL/J mice. Secretion of IL-4 and IL-5 by CD4(+) lymphocytes of BALB/c mice but not SJL/J mice was significantly augmented by ConA and reduced to control levels by curcumin. CONCLUSIONS: The efficacy of dietary curcumin in TNBS colitis varies in BALB/c and SJL/J mouse strains. Although the exact mechanism underlying these differences is unclear, the results suggest that the therapeutic value of dietary curcumin may differ depending on the nature of immune dysregulation in IBD

The Role of Curcumin in Modulating Colonic Microbiota During Colitis and Colon Cancer Prevention

BACKGROUND: Intestinal microbiota influences the progression of colitis-associated colorectal cancer (CAC). With diet being a key determinant of the gut microbial ecology, dietary interventions are an attractive avenue for the prevention of CAC. Curcumin is the most active constituent of the ground rhizome of the Curcuma Longa plant, which has been demonstrated to have anti-inflammatory, anti-oxidative and anti-proliferative properties. METHODS: Il10(−/−) mice on 129/SvEv background were used as a model of CAC. Starting at 10 weeks of age, WT or Il10(−/−) mice received six weekly i.p. injections of azoxymethane (AOM) or saline, and were started on either a control or curcumin-supplemented diet. Stools were collected every 4 weeks for microbial community analysis. Mice were sacrificed at 30 weeks of age. RESULTS: Curcumin-supplemented diet increased survival, decreased colon weight/length ratio, and at 0.5%, entirely eliminated tumor burden. Although colonic histology indicated improvement with curcumin, no effects of mucosal immune responses have been observed in PBS/Il10(−/−) mice, and limited effects were seen in AOM/Il10(−/−) mice. In WT and in Il10(−/−) mice, curcumin increased bacterial richness, prevented age-related decrease in alpha diversity, increased the relative abundance of Lactobacillales, and decreased Coriobacterales order. Taxonomic profile of AOM/Il10(−/−) mice receiving curcumin was more similar to those of wild-type mice than those fed control diet. CONCLUSIONS: In AOM/Il10(−/−) model, curcumin reduced or eliminated colonic tumor burden with limited effects on mucosal immune responses. The beneficial effect of curcumin on tumorigenesis was associated with the maintenance of a more diverse colonic microbial ecology