Shibata Wataru, Maeda Shin, Hikiba Yohko, Yanai Ayako, Ohmae Tomoya, Sakamoto Kei, Nakagawa Hayato, Ogura Keiji, Omata Masao
Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan.
J Immunol. 2007 Sep 1;179(5):2681-5. doi: 10.4049/jimmunol.179.5.2681.
Inflammatory mediators such as TNF-alpha, IL-6, and IL-1 are important in the pathogenesis of inflammatory bowel diseases and are regulated by the activation of NF-kappaB. The aim of the present study was to investigate whether the NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide, which has been shown to block the association of NEMO with the IkappaB kinasebeta subunit (IKKbeta) and inhibit NF-kappaB 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-kappaB 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-kappaB inhibition in both models. These results indicate that an IKKbeta-targeted NF-kappaB blockade using the NBD peptide could be an attractive therapeutic approach for inflammatory bowel disease.
肿瘤坏死因子-α、白细胞介素-6和白细胞介素-1等炎症介质在炎症性肠病的发病机制中起重要作用，并受核因子-κB激活的调控。本研究的目的是探讨核因子-κB必需调节因子（NEMO）结合结构域（NBD）肽是否能减轻结肠炎小鼠的炎症损伤，该肽已被证明可阻断NEMO与IκB激酶β亚基（IKKβ）的结合并抑制核因子-κB活性。通过以下方法建立了两种结肠炎模型：1）在小鼠饮用水中加入葡聚糖硫酸钠（DSS）；2）进行三硝基苯磺酸灌肠。在结肠组织中观察到明显的核因子-κB激活和促炎细胞因子的表达。在两种模型中，NBD肽通过抑制核因子-κB介导的促炎细胞因子下调，改善了结肠炎症损伤。这些结果表明，使用NBD肽靶向IKKβ的核因子-κB阻断可能是一种有吸引力的炎症性肠病治疗方法。
