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MFG-E8 Attenuates Intestinal Inflammation in Murine Experimental Colitis by Modulating Osteopontin-Dependent _vβ₃ Integrin Signaling¹

Md. Monowar Aziz^*, Shunji Ishihara^2,*, Yoshiyuki Mishima^*, Naoki Oshima^*, Ichiro Moriyama^*, Takafumi Yuki^*, Yasunori Kadowaki^*, Mohammad Azharul Karim Rumi, Yuji Amano and Yoshikazu Kinoshita^*

^* Department of Internal Medicine II, Shimane University School of Medicine, Shimane, Japan; Department of Pathology and Laboratory of Medicine, University of Kansas Medical Center, Kansas City, KS 66160; and Division of Gastrointestinal Endoscopy, Shimane University Hospital, Shimane, Japan

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 antiinflammatory mechanism, we employed an in vitro system, which showed the down-regulation of NF-B in an LPS-dependent manner. Additionally, MFG-E8 altered _vβ₃ 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 costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

² Address correspondence and reprint requests to Dr. Shunji Ishihara, Department of Internal Medicine II, Shimane University, Faculty of Medicine, 89-1, Enya-cho, Izumo, Shimane, Japan. E-mail address: si360405{at}med.shimane-u.ac.jp

³ Abbreviations used in this paper: UC, ulcerative colitis; CD, Crohn’s disease; IBD, inflammatory bowel disease; MFG-E8, milk fat globule-epidermal growth factor 8; DSS, dextran sodium sulfate; OPN, osteopontin; MPO, myeloperoxidase; FAK, focal adhesion kinase; RGD, arginine-glycine-aspartate; siRNA, small interfering RNA; EIA, enzyme immune assay; ECM, extracellular matrix protein; VN, vitronectin; FN, fibronectin.