Protection from experimental colitis by theaflavin‐3,3′‐digallate correlates with inhibition of IKK and NF‐κB activation

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Abstract
Background and purpose: 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.Experimental approach: Thein vivoefficacy 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.Key results: Oral administration of TFDG (5 mg kg−1daily i.g.) significantly improved TNBS‐induced colitis associated with decreased mRNA and protein levels of TNF‐α, IL‐12, IFN‐γand iNOS in colonic mucosa. DNA binding and Western blotting revealed increase in NF‐κB activation and IκBαdepletion in TNBS‐treated mice from Day 2 through Day 8 with a maximum at Day 4, which resulted from increased phosphorylation of IκBαand 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 IκBαin colon tissue.Conclusions and Implications: 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.British Journal of Pharmacology(2006)149, 121–131. doi:10.1038/sj.bjp.0706847