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Inflammatory bowel disease (IBD) is associated with activation of nuclear factor κ B (NF-κB) involved in regulating the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokine genes. As theaflavin-3,3′-digallate (TFDG), the most potent anti-oxidant polyphenol of black tea, down-regulates NF-κB activation, we investigated if TFDG is beneficial in colonic inflammation by suppressing iNOS and proinflammatory cytokines.The in vivo efficacy of TFDG was assessed in mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis. Both mRNA and protein levels of proinflammatory cytokines and iNOS were analyzed in colon tissue treated with or without TFDG. NF-κB activation was determined by electrophoretic mobility shift assay and levels of NF-κB inhibitory protein (IκBα) were analyzed by Western blotting.Oral administration of TFDG (5 mg kg−1 daily i.g.) significantly improved TNBS-induced colitis associated with decreased mRNA and protein levels of TNF-α, IL-12, IFN-γ and iNOS in colonic mucosa. DNA binding and Western blotting revealed increase in NF-κB activation and IκBα depletion in TNBS-treated mice from Day 2 through Day 8 with a maximum at Day 4, which resulted from increased phosphorylation of IκBα and higher activity of IκB kinase (IKK). Pretreatment with TFDG markedly inhibited TNBS-induced increases in nuclear localization of NF-κB, cytosolic IKK activity and preserved IκBα in colon tissue.TFDG exerts protective effects in experimental colitis and inhibits production of inflammatory mediators through a mechanism that, at least in part, involves inhibition of NF-κB activation.