MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent αvβ3 integrin signaling

MM Aziz, S Ishihara, Y Mishima, N Oshima… - The Journal of …, 2009 - journals.aai.org
MM Aziz, S Ishihara, Y Mishima, N Oshima, I Moriyama, T Yuki, Y Kadowaki, MAK Rumi…
The Journal of Immunology, 2009journals.aai.org
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 …
Abstract
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-κB in an LPS-dependent manner. Additionally, MFG-E8 altered α v β 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.
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