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Investigation regarding the role of MFG-E8 on NF-κB-dependent intestinal inflammation : Development of a new anti-inflammatory targeting MFG-E8

MFG-E8 对 NF-κB 依赖性肠道炎症作用的研究：开发新型抗炎靶向 MFG-E8

基本信息

批准号：
20590723
负责人：
ISHIHARA Shunji
金额：
$ 3.16万
依托单位：
Shimane University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590723/
关键词：
炎症性腸疾患自然免疫 MFG-E8 Toll受容体 NF-κB Tool受容体 MF-κB MF-кB

项目摘要

MFG-E8 deficiency is associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. We observed altered MFG-E8 expression in inflamed colons during the acute phase of murine experimental colitis and found that treatment with recombinant MFG-E8, but not its RGD mutant counterpart, ameliorated colitis by reducing inflammation and improving disease parameters. To reveal the MFG-E8-mediated anti-inflammatory mechanism, we employed an in vitro system, which showed the downregulation of NF-κB in an LPS dependent manner. In addition, MFG-E8 altered α_vβ_3-integrin-mediated FAK phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis.Recently, we also employed mfg-e8 KO mice for evaluating the function of MFG-E8 on intestinal inflammation. Acute experimental colitis was established by administrating of dextran sodium sulphate (DSS). We found that exacerbation of body weight loss, shorting of colon and histological inflammation in mfg-e8 KO mice during DSS-induced intestinal inflammation, as compared to those in wild mice. Additional investigations will be necessary to elucidate the role of MFG-E8 in chronic intestinal inflammation.

MFG-E8缺乏与由于组织稳态丧失而获得免疫介导的疾病有关。在小鼠实验性结肠炎的急性期，我们观察到炎症结肠中MFG-E8表达的改变，发现用重组MFG-E8治疗，而不是用RGD突变体治疗，通过减少炎症和改善疾病参数来改善结肠炎。为了揭示mfg - e8介导的抗炎机制，我们采用体外系统，显示NF-κB以LPS依赖的方式下调。此外，MFG-E8通过阻碍其强效配体骨桥蛋白的结合而改变α_vβ_3整合素介导的FAK磷酸化，骨桥蛋白在结肠炎期间被激活。我们的研究结果表明，MFG-E8在治疗结肠炎方面具有新的治疗潜力。最近，我们还利用mfg-e8 KO小鼠来评估mfg-e8对肠道炎症的作用。用葡聚糖硫酸钠（DSS）建立急性实验性结肠炎。我们发现，与野生小鼠相比，mfg-e8 KO小鼠在dss诱导的肠道炎症期间体重减轻、结肠缩短和组织学炎症加剧。需要进一步的研究来阐明MFG-E8在慢性肠道炎症中的作用。