Glucagon-like peptide 2 (GLP-2) is an important intestinal growth factor with anti-inflammatory activity. We hypothesized that GLP-2 decreases mucosal inflammation and the associated increased epithelial proliferation by down regulation of Th1 cytokines due to reprogramming of lamina propria immune regulatory cells, via an Interleukin-10 (IL-10) independent pathway. The effects of GLP-2 treatment were studied using the IL-10 deficient (IL-10^-/-) mouse model of colitis. Wild type and IL-10^-/- mice received saline or GLP-2 (50 µg/kg/sc. injection) treatment for 5 days. GLP-2 treatment resulted in significant amelioration of animal weight loss, and reduced intestinal inflammation as assessed by histopathology and myeloperoxidase levels compared to saline treated animals. In colitis animals, GLP-2 treatment also reduced crypt cell proliferation and crypt cell apoptosis. Pro-inflammatory (IL-1, TNF-, IFN-,) cytokine protein levels were significantly reduced after GLP-2 treatment, while IL-4 was significantly increased, and IL-6 production was unchanged. FACS analysis of lamina propria cells demonstrated a decrease in the CD4⁺ T cell population following GLP-2 treatment in colitic mice and an increase in CD11b⁺/F4/80⁺ macrophages, but no change in CD25+FoxP3 T-cells or CD11c⁺ dendritic cells. In colitis animals intracellular cytokine analysis demonstrated GLP-2 decreased lamina propria macrophage TNF- production, but increased IGF-1 production while TGF- was unchanged. GLP-2 mediated reduction of crypt cell proliferation was associated with an increase in intestinal epithelial cell SOCS-3 expression and reduced STAT-3 signaling. This study shows that the anti-inflammatory effects of GLP-2 are IL-10 independent, and that GLP-2 alters the mucosal response of inflamed intestinal epithelial cells and macrophages. In addition, the suggested mechanism of the reduction in inflammation induced proliferation is due to GLP-2 activation of the SOCS-3 pathway, which antagonizes the IL-6 mediated increase in STAT-3 signalling.