Division of Infection, Inflammation and Repair, University of Southampton, School of Medicine, Southampton, UK; Department of Gastroenterology, Royal Hampshire County Hospital, Winchester, UK.
J Crohns Colitis. 2009 Sep;3(3):175-82. doi: 10.1016/j.crohns.2009.03.001. Epub 2009 Apr 10.
Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied.
To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD.
Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA.
CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs.
These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohn's disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.
沙利度胺（thalidomide）是一种能够抑制肿瘤坏死因子（TNF）-α生成的药物，据报道其对难治性炎症性肠病（IBD）具有治疗效果。肠道固有层单核细胞（LPMCs）中 TNF-α驱动的基质金属蛋白酶（MMP）-3生成是 IBD 组织损伤的主要途径；然而，尚未研究沙利度胺和更新的更有效的免疫调节衍生物对这一途径的影响。
研究沙利度胺、CC-4047（泊马度胺）、CC-5013（来那度胺）和 CC-10004（阿普司特）对 IBD 患者肠道 LPMC TNFα和 MMP-3 生成的影响。
从 IBD 患者中分离肠道 LPMCs 和肌成纤维细胞，并在沙利度胺、CC-4047、CC-5013 和 CC-10004 的作用下进行培养。通过 Western blot 和实时 PCR 测定 MMP-3 和 TIMP-1 水平，并通过 ELISA 测定 TNF-α水平。
CC-10004 显著降低了培养的 LPMCs 中 TNF-α和 MMP-3 的生成。沙利度胺和 CC-4047 及 CC-5013 对 LPMCs 中 TNF-α或 MMP-3 的生成没有显著影响。
这些结果为来那度胺（CC-5013）在最近的克罗恩病随机对照试验中的失败以及 CC-10004 作为一种新型口服治疗 CD 和 UC 的药物的评估提供了机制依据。
