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Cutting Edge: The IB Kinase (IKK) Inhibitor, NEMO-Binding Domain Peptide, Blocks Inflammatory Injury in Murine Colitis¹

Wataru Shibata^*,, Shin Maeda^2,*,, Yohko Hikiba^*, Ayako Yanai^*, Tomoya Ohmae, Kei Sakamoto, Hayato Nakagawa, Keiji Ogura and Masao Omata

^* Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan; and Department of Gastroenterology, University of Tokyo, Tokyo, Japan

Inflammatory mediators such as TNF-, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-B. The aim of the present study was to investigate whether the NF-B essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IB kinase subunit (IKK) and inhibit NF-B activity, reduces inflammatory injury in mice with colitis. Two colitis models were established by the following: 1) inclusion of dextran sulfate sodium salt (DSS) in the drinking water of the mice; and 2) a trinitrobenzene sulfonic acid enema. Marked NF-B activation and expression of proinflammatory cytokines were observed in colonic tissues. The NBD peptide ameliorated colonic inflammatory injury through the down-regulation of proinflammatory cytokines mediated by NF-B inhibition in both models. These results indicate that an IKK-targeted NF-B blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid 17209026 and 18890244 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

² Address correspondence and reprint requests to Dr. Shin Maeda, Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan. E-mail address: shinmaeda2-gi{at}umin.ac.jp

³ Abbreviations used in this paper: IBD, inflammatory bowel disease; APDC, ammonium pyrrolidine dithiocarbamate; Cox-2, cyclooxygenase-2; DSS, dextran sulfate sodium salt; Et-OH, ethanol; IKK, IB kinase; NEMO, NF-B essential modulator; NBD, NEMO-binding domain; mutNBD, mutated NBD; TNBS, trinitrobenzene sulfonic acid; wtNBD, wild-type NBD.

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