Abstract
We investigated the role of the PI3K p85α subunit in the development of acute colitis with a focus on intestinal macrophages. Experimental acute colitis was induced using 3% dextran sulfate sodium (DSS) in drinking water for 7 days. The severity of DSS-induced acute colitis was significantly attenuated in p85α hetero-deficient (p85α+/−) mice compared with WT mice. The expression of proinflammatory mediators in intestinal macrophages isolated from the inflamed colonic mucosa was significantly suppressed in p85α+/− colitis mice compared with WT colitis mice. Interestingly, we found that bone marrow-derived macrophages (BMDMs) from p85α+/− mice produced a significantly higher amount of IL-10 than BMDMs from WT mice. The adoptive transfer of p85α+/− BMDMs, but not WT BMDMs, significantly improved the severity in WT colitis mice, and this effect was reversed by anti-IL-10 antibody. Furthermore, the expression of IL-10 in the intestinal macrophages of p85α+/− normal colonic mucosa was significantly higher than that in the intestinal macrophages of WT normal colonic mucosa. The present results demonstrate that p85α+/− mice exhibit a reduced susceptibility to DSS-induced acute colitis. Our study suggests that a deficiency of PI3K p85α enhances the production of IL-10 in intestinal macrophages, thereby suppressing the development of DSS-induced acute colitis.
Highlights
Inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis are chronic inflammatory disorders[1]
We demonstrated that p85α hetero-deficient (p85α+/−) mice exhibited a reduced susceptibility to dextran sulfate sodium (DSS)-induced acute colitis through an enhancement of IL-10 production
To clarify the role of the p85α subunit in colitis, we examined the development of DSS-induced acute colitis in WT and p85α+/− mice
Summary
Several studies have reported a role for PI3K in colitis in humans and animal models. We report that mice deficient in the p85α subunit exhibit a reduced susceptibility to DSS-induced acute colitis due to the augmentation of IL-10 production by intestinal macrophages in the colonic mucosa. Distributed in the colonic lamina propria in a proportion equivalent to that in a previous report[31] These results strongly indicate that p85α deficiency in mice enhances the IL-10 production of intestinal macrophages, resulting in the suppression of acute colitis development. The present study demonstrated that no difference in Akt and GSK-3β phosphorylation was induced by LPS stimulation between WT and p85α+/− BMDMs. we observed that PI3K inhibitor treatment at the effective concentration for the inhibition of Akt activation reduced IL-10 production in BMDMs, which is consistent with previous finding[33]. The augmentation of IL-10 production in intestinal macrophages has the potential to be a novel therapeutic target for IBD
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