Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
Dept. of Medicinal Chemistry, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
Cytokine. 2014 Mar;66(1):30-9. doi: 10.1016/j.cyto.2013.12.010. Epub 2014 Jan 4.
TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation. Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.
肿瘤坏死因子-α 转化酶（TACE）将细胞膜 TNF-α 加工为具有生物活性的可溶性 TNF-α。有几项证据表明 TNF-α 和 TACE 参与了炎症性肠病（IBD）。组织金属蛋白酶抑制剂（TIMP）-3 是 TACE 的内源性抑制剂，与沉默信息调节因子（SIRT）-1 呈正相关。我们旨在研究 TACE、TIMP-3 和 SIRT-1 在结肠炎不同阶段的表达，以及 TACE 如何响应 SIRT-1 激活而受到调节。通过在饮用水中添加 3.5%葡聚糖硫酸钠（DSS）诱导急性结肠炎，在不同时间点测量结肠中细胞因子和 TACE、TIMP-3 和 SIRT-1 的 mRNA 表达水平。接下来，评估 SIRT-1 激活剂（白藜芦醇）或选择性 TACE 抑制剂（化合物 11p）的治疗效果。在 DSS 暴露期间观察到 TNF-α、白细胞介素（IL）-6、IL-1β、干扰素（IFN）-γ 和 IL-17 水平升高，在 DSS 去除后恢复到正常水平。在 DSS 暴露期间，TACE 显著增加，TIMP-3 和 SIRT-1 mRNA 水平受到抑制，在缓解期恢复正常。白藜芦醇治疗可显著提高 SIRT-1 和 TIMP-3 的水平，并抑制 TACE mRNA 表达，与疾病改善相关。此外，选择性 TACE 抑制剂治疗可显著抑制 DSS 挑战后体重减轻、疾病活动指数、结肠髓过氧化物酶活性和细胞因子水平升高。这些结果强烈强调了 TACE 在结肠炎症中的作用，通过直接或间接激活 SIRT-1 抑制 TACE 可改善结肠炎。
