Modulation of Dextran Sulphate Sodium-Induced Colonic Inflammation by Local Supplementation of Leptin~!2008-08-10~!2008-10-20~!2008-12-05~!

Background & Aims: Leptin is overproduced in gastrointestinal mucosa during inflammatory processes, sug- gesting that mucosal cells represent sources of secreted leptin active in the lumen. The effects of leptin, acting apically from colonic epithelial cells, were analysed on dextran sulphate sodium-induced colonic inflammation in rats. Methods: We determined the effects of intracolonic leptin on the phosphorylation of STAT3, MAPkinase and on colon mucosa-derived inflammation-related genes (IL-8, IL1, TNF, COX-2). Colitis was induced by administering dextran sodium sulphate. The effects of intracolonic leptin on DSS colitis was evaluated based on disease symptoms, cytokine ex- pression and PPAR  ,  . Results: In vivo, intracolonic leptin rapidly stimulated STAT-3 and p42-MAPK phosphorylation. We also detected a 3- fold increase in COX-2 induction, and a dose-dependent increase in mucosal PGE2 content (EC50 0.89 nM). Intracolonic leptin reduced the severity of DSS-induced colitis, whereas intraperitoneal leptin exacerbated colitis. Intracolonic leptin decreased DSS-induced inflammatory IL-8 (-75%; P<0.01 vs DSS) and IL-1 (-60%; P<0.01 vs DSS); it also prevented a DSS-induced decrease in the levels of mucosa PPAR mRNA and increased the levels of PPARmRNA two-fold (P<0.01 vs DSS). Conclusion: Leptin activates its apical receptor and this mechanism coupled to the activation of STAT-3 and MAPKinase signalling pathways may have a beneficial effect on the integrity of the epithelium upon mucosa injury. These data shed further light on the role of gastrointestinal luminally acting leptin in the modulation of intestinal inflammation.