Sirolimus ameliorates inflammatory responses by switching the regulatory T/T helper type 17 profile in murine colitis

Inflammatory bowel disease is characterized by dysregulated immune responses in inflamed intestine, with dominance of interleukin-17 (IL-17) -producing cells and deficiency of regulatory T (Treg) cells. The aim of this study was to investigate the effect and mechanisms of sirolimus, an inhibitor of the mammalian target of rapamycin, on immune responses in a murine model of Crohn's disease. Murine colitis was induced by intra-rectal administration of 2,4,6-trinitrobenzene sulphonic acid at day 0. Mice were then treated intraperitoneally with sirolimus daily for 3 days. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. Sirolimus treatment significantly decreased all macroscopic, microscopic and histopathological parameters of colitis that were analysed. The therapeutic effects of sirolimus were associated with a down-regulation of pro-inflammatory cytokines tumour necrosis factor-alpha, IL-6 and IL-17A. Intriguingly, sirolimus administration resulted in a prominent up-regulation of the regulatory cytokine transforming growth factor-beta. Supporting the hypothesis that sirolimus directly affects the functional activity of CD4(+) CD25(+) Treg cells, we observed a remarkable enhancement of FoxP3 expression in colon tissues and isolated CD4(+) T cells of sirolimus-treated mice. Simultaneously, sirolimus treatment led to a significant reduction in the number of CD4(+) IL-17A(+) T cells in the mesenteric lymph node cells as well as IL-17A production in mesenteric lymph node cells. Therefore, sirolimus may offer a promising new therapeutic strategy for the treatment of inflammatory bowel disease.