Inflammatory bowel disease (IBD) refers to chronic idiopathic inflammatory diseases of the intestine, principally ulcerative colitis and Crohn's disease. No disease-specific therapy is available, and current medical management of IBD consists of anti-inflammatory and immunosuppressive agents. Despite medical intervention, nearly 1/3 of patients remain refractory. Chronic conditions, such as IBD, are commonly associated with the use of alternative medicine. In IBD, duration of disease and ineffectiveness of medical treatments correlate with alternative medicine use. Clearly, new therapeutic modalities are needed to minimize the destructive nature of IBD, and scientifically proven efficacious alternative medicine would be an accepted approach. It is our working hypothesis that the transcription factor, nuclear factor -kappaB (NF-kappaB) and NF-kappaB-inducible inflammatory mediators (e.g. tumor necrosis factor-a, interleukin-1, and adhesion molecules) play a critical role in the intestinal injury and many of the clinical/biochemical abnormalities observed in IBD. In support of this, increased NF- kappaB has been demonstrated in inflamed mucosa of IBD patients and studies using inhibitors of NF-kappaB have attenuated inflammation in animal models. We recently showed that polyphenols extracted from green tea are potent inhibitors of NF- kappaB. We present exciting preliminary data showing that the green tea polyphenol, (-)-epigallocatechin-3-gallate, inhibits the activity of IkappaB kinase (IKK), a pivotal enzyme in the NF- kappaB activation pathway. The overall objective of this project is to determine whether green tea polyphenols modulate intestinal injury and immune cell responses in IBD. Specifically, we will determine whether or not green tea polyphenols, in doses ranging from that considered functional food to pharmacological, ameliorate intestinal injury in the interleukin-2 deficient mouse model of IBD. We will also compare the efficacy of green tea polyphenols to that of sulfasalazine, an accepted therapy for IBD, and to that of vitamin E, an antioxidant with anti- inflammatory properties, in modulating intestinal injury in the murine model of 2,4,6-trinitrobenzene sulfonic acid-induced colitis. These studies should provide evidence supporting green tea/green tea polyphenols as potent anti-inflammatory therapy and provide the basis for future human studies in IBD. This submission supplements K08 DK02401-01A1.
