Pegylated leptin antagonist ameliorates chronic colitis by inducing regulatory T cells (Tregs) partially mediated by TGF-beta induction (162.4)

Abstract IIBD is a chronic intestinal inflammation caused by hyper activated effector immune cells that affects millions of people around the world. Several lines of evidence support an important role for TGF-beta in the induction of tolerance and control gut inflammation. Leptin is satiety hormone produced primarily by adipose tissue, which increases during IBD progression. We investigated the effect of pegylated leptin antagonist mediated inhibition of chronic colitis in IL-10-/- mice. In the present study, we report that pegylated leptin antagonist (mutant L39A/D40A/F41A) effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis including a decrease in body weight, systemic serum amyloid A (SAA), and leptin levels. The percentage of Tregs in the spleen, mesenteric lymph node (MLN) and intestinal lamina propria (LP) of colitis mice was increased after leptin antagonist treatment as compared to control mice. Similarly, the percentage of TGF-beta in the MLN and LP of colitis mice increased after leptin antagonist treatment. Leptin antagonist also reduced systemic and mucosal cytokines as well as increased the insulin level as compared to control mice. These findings suggest that leptin antagonist ameliorates chronic colitis by inducing TGF-beta, which mediates the induction of Tregs and reduces both mucosal and systemic cytokines. The intricate interaction among leptin, TGF-beta and Tregs might provide new strategies for therapeutic interventions.