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First published on January 11, 2006; DOI: 10.1124/mol.105.020578

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Received for publication November 7, 2005.
Revised December 15, 2005.
Accepted for publication January 3, 2006.

A molecular mechanism for the anti-inflammatory effect of taurine-conjugated 5-aminosaliylic acid in inflamed colon

Heejung Kim 1, Hyunchu Jeon 1, Hyesik Kong 2, Youngwook Yang 3, Boim Choi 3, Young Mi Kim 3, Len Neckers 2, Yunjin Jung 1*

1 Laboratory of Biomedicinal Chemistry, College of Pharmacy, Pusan National University 2 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH 3 Laboratory of Medicinal Chemistry, College of Pharmacy, Pusan National University

* Address correspondence to: E-mail: jungy{at}pusan.ac.kr

Abstract

In previous reports, a novel colon specific prodrug, 5- aminosalicyltaurine (5-ASA-Tau) administered orally, is successfully delivered to and liberates 5-aminosalicylic acid and taurine in the inflamed large intestine of rats. Furthermore, the prodrug ameliorates the TNBS-induced colitis and taurine acts not only a carrier but also an active therapeutic agent. In this study, we investigated the anti-inflammatory properties of the prodrug at a molecular level. After rectal administration of taurine, formation of taurine chloramine (TauCl) in the inflamed colonic tissue was examined using HPLC. In human colon epithelial cell lines, NF{kappa}B activity was accessed using an NF{kappa}B-dependent luciferase reporter gene. Protein levels were monitored by Western blotting. DNA binding activity of the NF{kappa}B subunit p65 was determined using a DNA binding assay kit. Millimolar level of TauCl was formed in the inflamed tissue. TauCl inhibited TNF-dependent NF{kappa}B activation by modifying thiol(s) on p65 and blocking DNA binding. In addition, 5-ASA inhibited phosphorylation of p65 at serine 536 which is critical for transcriptional activity of NF{kappa}B. Furthermore, combined TauCl/5-ASA treatment additively inhibited TNF-dependent NF{kappa}B activation. Taken together, our data suggest that the colon specific carrier taurine contributes to the clinical effect of the prodrug by potentiating the inhibitory effect of the active ingredient 5-ASA on a major pro-inflammatory signal, TNF-dependent NF{kappa}B activation in the inflamed large intestine.


Key words: Tumor necrosis factor, NFkappaB, Cyclooxygenases




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