MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling.
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-kappaB 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.
Aziz
Md Monowar
MM
Department of Internal Medicine II, Shimane University School of Medicine, Shimane, Japan.
Ishihara
Shunji
S
Mishima
Yoshiyuki
Y
Oshima
Naoki
N
Moriyama
Ichiro
I
Yuki
Takafumi
T
Kadowaki
Yasunori
Y
Rumi
Mohammad Azharul Karim
MA
Amano
Yuji
Y
Kinoshita
Yoshikazu
Y
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000494:pharmacology*; D003092:Colitis; D004195:Disease Models, Animal; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D007249:Inflammation; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D051379:Mice; D008894:Milk Proteins / Q000032:analysis / Q000494:pharmacology*; D016328:NF-kappa B / Q000032:analysis; D053495:Osteopontin / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects
D000954:Antigens, Surface; D039302:Integrin alphaVbeta3; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D016328:NF-kappa B; D053495:Osteopontin; D051416:Focal Adhesion Protein-Tyrosine Kinases