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Protection from experimental colitis by theaflavin-3,3'-digallate correlates with inhibition of IKK and NF-kappaB activation.

AbstractBACKGROUND AND PURPOSE:
Inflammatory bowel disease (IBD) is associated with activation of nuclear factor kappa B (NF-kappaB) 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-kappaB activation, we investigated if TFDG is beneficial in colonic inflammation by suppressing iNOS and proinflammatory cytokines.
EXPERIMENTAL APPROACH:
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-kappaB activation was determined by electrophoretic mobility shift assay and levels of NF-kappaB inhibitory protein (IkappaBalpha) were analyzed by Western blotting.
KEY RESULTS:
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-alpha, IL-12, IFN-gamma and iNOS in colonic mucosa. DNA binding and Western blotting revealed increase in NF-kappaB activation and IkappaBalpha depletion in TNBS-treated mice from Day 2 through Day 8 with a maximum at Day 4, which resulted from increased phosphorylation of IkappaBalpha and higher activity of IkappaB kinase (IKK). Pretreatment with TFDG markedly inhibited TNBS-induced increases in nuclear localization of NF-kappaB, cytosolic IKK activity and preserved IkappaBalpha in 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-kappaB activation.
AuthorsA Ukil, S Maity, P K Das
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 149 Issue 1 Pg. 121-31 (Sep 2006) ISSN: 0007-1188 [Print] England
PMID16880762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Biflavonoids
  • Flavonoids
  • I-kappa B Proteins
  • NF-kappa B
  • Phenols
  • Polyphenols
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Ether
  • Interleukin-12
  • Nitric Oxide
  • theaflavin digallate
  • Gallic Acid
  • Interferon-gamma
  • Catechin
  • Trinitrobenzenesulfonic Acid
  • Peroxidase
  • Nitric Oxide Synthase Type II
Topics
  • Animals
  • Biflavonoids (pharmacology)
  • Biotransformation (drug effects)
  • Catechin (pharmacology)
  • Cell Nucleus (drug effects, metabolism)
  • Colitis (chemically induced, prevention & control)
  • Cytoplasm (drug effects, metabolism)
  • Ether
  • Female
  • Flavonoids (pharmacology)
  • Gallic Acid (analogs & derivatives, pharmacology)
  • I-kappa B Proteins (drug effects)
  • Interferon-gamma (biosynthesis)
  • Interleukin-12 (biosynthesis)
  • Macrophages (drug effects)
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B (drug effects, metabolism)
  • Nitric Oxide (biosynthesis)
  • Nitric Oxide Synthase Type II (biosynthesis)
  • Peroxidase (metabolism)
  • Phenols (pharmacology)
  • Polyphenols
  • RNA, Messenger (biosynthesis)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trinitrobenzenesulfonic Acid
  • Tumor Necrosis Factor-alpha (biosynthesis)

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