MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent αvβ3 Integrin Signaling
MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent αvβ3 Integrin Signaling
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DOI：
10.4049/jimmunol.0803711
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发表时间：
2009-06-01
影响因子：
4.4
通讯作者：
Kinoshita, Yoshikazu
中科院分区：
文献类型：
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作者：
Aziz, Md. Monowar;Ishihara, Shunji;Kinoshita, Yoshikazu
MFG-E8（乳脂球-表皮生长因子8）缺乏与由于组织稳态丧失而导致的免疫介导的疾病的获得密切相关。然而，关于其在胃肠道疾病中的功能知之甚少，其中免疫稳态是一个主要问题。在本文中，我们报告了在小鼠实验性结肠炎急性期期间发炎结肠中MFG-E8表达的改变，并且发现用重组MFG-E8治疗，而不是其精氨酸-甘氨酸-天冬氨酸突变体对应物，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，其显示NF-κ B以LPS依赖性方式下调。此外，MFG-E8通过阻碍其一种有效配体骨桥蛋白的结合来改变α（v）β（3）整合素介导的粘着斑激酶磷酸化，骨桥蛋白在结肠炎期间被激活。总之，我们的结果表明MFG-E8具有治疗结肠炎的新治疗潜力。免疫学杂志，2009，182：7222-7232.
MFG-E8 (milk fat globule-epidermal growth factor 8) deficiency is strongly associated with acquisition of immune-mediated disorders due to the loss of tissue homeostasis. However, comparatively little is known regarding its functions in gastrointestinal tract disorders, in which immune homeostasis is a major concern. Herein, we report 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 arginine-glycine-aspartate 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 down-regulation of NF-kappa B in an LPS-dependent manner. Additionally, MFG-E8 altered alpha(v)beta(3) integrin-mediated focal adhesion kinase phosphorylation by impeding the binding of one of its potent ligands osteopontin, which becomes activated during colitis. Taken together, our results indicated that MFG-E8 has a novel therapeutic potential for treatment of colitis. The Journal of Immunology, 2009, 182: 7222-7232.