Abstract
Colitis is a major form of inflammatory bowel disease which involved mucosal immune dysfunction. Aloperine is an alkaloid isolated from the shrub Sophora alopecuroides L. and has been recognized as an effective treatment for inflammatory and allergic diseases. The present study aimed to examine the molecular mechanisms underlying aloperine-mediated colitis protection. We found that aloperine treatment improved colitis induced by dextran sodium sulfate (DSS) based on body weight, disease activity index, colonic length, and spleen index. Aloperine also effectively attenuated DSS-induced intestinal inflammation based on the pathological score and myeloperoxidase expression and activity in colon tissues. In addition, aloperine regulated T-cell proportions and promoted Foxp3 expression in the spleens and mesenteric lymph nodes of DSS-induced colitis mice and in the spleens of the Foxp3GFP mice. Aloperine inhibited Jurkat and mouse naïve T-cell apoptosis. Furthermore, aloperine inhibited PI3K/Akt/mTOR signaling and upregulated PP2A expression in the DSS-induced colitis mice and in Jurkat cells, but LB-100 (PP2A inhibitor) resulted in an elevated Akt activity in Jurkat cells, activated T-cells, and human splenic mononuclear cells. Aloperine inhibited T-cell and lymphocyte proliferation, but LB-100 reverse these effects. In conclusion, aloperine regulates inflammatory responses in colitis by inhibiting the PI3K/Akt/mTOR signaling in a PP2A-dependent manner.
Highlights
Inflammatory bowel disease (IBD) is a familial spontaneous autoimmune disease, but its pathogenesis remains enigmatic
phosphatase 2A (PP2A) has been shown to enhance the inflammatory effects of a number of compounds [36, 37] and PP2A activation attenuates inflammation in animal models [38, 39]. These results were consistent with the present study, wherein we showed that PP2A expression declined in colitis and LB-100 increased the expression of forkhead box P3 (Foxp3) in mouse naïve T-cells and Tregs
We demonstrated that aloperine suppressed PI3K/AkT/ mTOR signaling, a pathway that positively regulates T-cell functions [9, 41, 42]
Summary
Inflammatory bowel disease (IBD) is a familial spontaneous autoimmune disease, but its pathogenesis remains enigmatic. Especially the overexpression of T-cells, plays a major role in IBD pathogenesis [3]. Th17 cells may enhance intestinal inflammation, whereas Tregs might inhibit the inflammatory responses [6]. The differentiation of Tregs is modulated by the expression of the lineage-specific transcription factor forkhead box P3 (Foxp3), which can suppress autoimmune diseases in normal individuals. Tregs regulate the immune system by secreting suppressive cytokines such as tumor growth factor- (TGF-) β and interleukin- (IL-) 10 [7]. PI3K/Akt/mTOR signaling negatively modulates Treg functions and is involved in several diseases including cancer, ischemic disease, and Mediators of Inflammation inflammation [8, 9]. An effective inhibitor of the PI3K/Akt/ mTOR pathway might contribute to the treatment of IBD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
