W1672 Exacerbation of Indomethacin-Induced Small Intestine Injuries in Reg I-Knockout Mice

PI3K-dependent, while Ser644 phosphorylation required IKK.These phosphorylation events were associated with a 45% decrease in nuclear Foxo3a.Also data suggest that IEC Foxo3a regulation by TNFα occurs via separate PI3K-and IKK-dependent pathways that trigger translocation to the cytosol and proteasomal degradation.We used DSS-treatment to assess the role of Foxo3a in intestinal inflammation.Prominent nuclear Foxo3a staining in control colonic epithelia was lost in DSS-treated colonic epithelia where Foxo3a is in the cytosol, suggesting that in proinflammatory conditions Foxo3a is inactivated.In Foxo3a KO mice DSS induced injury was significantly more severe and recovery was poorer, relative to WT mice (Histology score: KO 5.0+0.1 vs WT 3.2+0.2),and associated with broad areas of mucosal ulceration.Summary: These data indicate that Foxo3a plays an important role in controlling intestinal inflammation.Therefore Foxo3a is a potential target for treatment of intestinal inflammation of patients with inflammatory bowel disease.