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

Abstract

BACKGROUND 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.

• Authors: A Ukil, S Maity, P K Das
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 149 Issue 1 Pg. 121-31 (Sep 2006) ISSN: 0007-1188 [Print] England
• PMID: 16880762 (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)