Protective Effects of Dietary Curcumin in Mouse Model of Chemically Induced Colitis Are Strain Dependent

Idiopathic inflammatory bowel diseases [IBD; Crohn’s disease (CD) and ulcerative colitis (UC)] are defined as autoimmune diseases implicated in aberrant and persistent inflammation of the bowel because of an excessive effector response or an insufficient regulatory response to commensal bacterial flora.1 Both environmental factors and genetic predisposition have been implicated in the pathogenesis of CD and UC, although their precise contributions remain incompletely understood.1–4 Although both CD and UC share a common basis in immune hyperresponsiveness to mucosal antigens, the 2 diseases vary considerably. Crohn’s disease is associated with a Th1/Th17 cell–mediated response mediated by IL-12 and IL-23, with concomitant increased production of IFNγ, IL-2, IL-18, and IL-17,1,5–7 whereas ulcerative colitis is associated with an atypical Th2 response characterized by NKT secretion of IL-13 accompanied by increased production of IL-4 and IL-5.1,8 Both in human IBD and in animal models of the disease, the development and persistency of inflammation depend partially on the activation and nuclear translocation of the NFκB complex. Although with somewhat different mechanisms, NFκB regulates transcription of both Th1/Th17-associated cytokines like IL-12 and IL-239–12 and the Th2 cytokines IL-4 and IL-13,13,14 making NFκB an attractive therapeutic target in both CD and UC. In fact, decoy oligonucleotides containing NFκB-binding sites were proven effective in both the prevention and treatment of murine Th1 and Th2 models of hapten-induced colitis.15 Curcumin (diferulolylmethane) is also an emerging candidate drug targeting, among other pathways, the signaling events leading to NFκB activity.16 The effects of curcumin on the immune response (both innate and adaptive) has been a subject of much attention in the past decade.17 Curcumin has been identified as the most active constituent of turmeric and has been described as an anti-inflammatory, antioxidant, proapoptotic, and antiproliferative compound.18–21 In addition, this compound regulates the activity of several enzymes via direct interaction or can modulate gene transcription through the inhibition of transcription factors and signaling pathways.22 Curcumin has been shown to play a protective role in chemically induced mouse models of IBD23–26 and to reduce the relapse rate in human UC.27 Colitis can be efficiently induced in mice using a rectally administered haptenizing agent, trinitrobenzene sulfonic acid (TNBS) in 50% ethanol, with the nature of the immune response to TNBS depending on the genetic background of the mice used. In BALB/c mice, TNBS colitis develops independently of IFNγ, with prominent Th2 responses in colonic patches and lesions.28 Although Th1 response and IFNγ has been implicated in the early deaths of TNBS-treated BALB/c mice, in later stages of the disease in this strain, expression of IFNγ mRNA in CD4+ cells is undetectable, whereas morphological changes in the colonic mucosa are reminiscent of those observed in ulcerative colitis.28 In contrast, TNBS-induced colitis in SJL/J mice is mediated by Th1-type T cells and is associated with high production of IL-12 and IFNγ. This response may be attributed to a susceptibility locus on chromosome 11 of SJL/J mice, associated with increased IL-12 responses to parenteral injection of LPS.29 The importance of IL-12 and/or IL-23 was demonstrated by the efficacy of a single injection of anti-p40 antibody in preventing colitis.30 Colitis in SJL/J mice can also be prevented by the administration of anti-CD40, blocking CD40–CD40L interactions, which are crucial in Th1-mediated inflammation.31,32 The key role of TNFα in TNBS colitis in the SJL/J strain also confirms the importance of the Th1 pathway because TNFα-deficient mice do not develop inflammation.33 The Th1-skewed response to TNBS in SJL/J mice is likely a result of a defect in NKT cells that have been implicated in IL-13 production and associated with an atypical Th2 response in ulcerative colitis.8 SJL/J mice have drastically reduced the number of B220−/CD1d tetramer+ NKT cells34 with defective T-cell-receptor-induced IL-4 production and absence of T cells expressing NK1.1.35 In this study, we investigated the effect of dietary curcumin in a concentration previously demonstrated as effective in BALB/c mice (2%)25 in the 2 strains of mice: SJL/J and BALB/c. This model of hapten-induced colitis allows the study of the initial event in the development of mucosal inflammation, associating the response to specific antigen (in the presence of ethanol) and the mucosal immune response leading to colonic inflammation. Our results indicate that in BALB/c mice, which exhibit a mixed Th1/Th2 response, dietary curcumin significantly increases survival, protects from weight loss, and normalizes the indices of the disease, while remaining ineffective in Th1-skewed SJL/J mice. Using a genomewide microarray analysis of colonic gene expression, we identified a differential pattern of genes regulated by dietary curcumin in these 2 mouse strains. Moreover, in vitro, curcumin inhibits concanavalin A (ConA)–induced proliferation of splenocytes from naive BALB/c mice but not SJL/J mice. The curcumin IC for CD4+ 50 T-cell proliferation was 2-fold higher in SJL/J mice than in BALB/c mice. Our results therefore provide a side-by-side comparison of the effectiveness of curcumin in 2 immunologically distinct models of chemically induced colitis and may suggest potential differences in the usefulness of this compound in Crohn’s disease and ulcerative colitis.