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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/G1202    most recent 90494.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Ivory, C. P. A. Articles by Sigalet, D. L. PubMed PubMed Citation Articles by Ivory, C. P. A. Articles by Sigalet, D. L.

INFLAMMATION/IMMUNITY/MEDIATORS

Interleukin-10-independent anti-inflammatory actions of glucagon-like peptide 2

Faculty of Medicine, Gastrointestinal Research Group, Institute of Infection, Immunity and Inflammation, Faculty of Medicine, University of Calgary, Health Sciences Centre, Calgary, Alberta, Canada

Submitted 13 August 2008 ; accepted in final form 3 October 2008

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 downregulation of Th1 cytokines attributable 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) 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 with saline-treated animals. In colitis animals, GLP-2 treatment also reduced crypt cell proliferation and crypt cell apoptosis. Proinflammatory (IL-1β, TNF-, IFN-,) cytokine protein levels were significantly reduced after GLP-2 treatment, whereas IL-4 was significantly increased and IL-6 production was unchanged. Fluorescence-activated cell sorting 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 that GLP-2 decreased lamina propria macrophage TNF- production but increased IGF-1 production, whereas transforming growth factor-β was unchanged. GLP-2-mediated reduction of crypt cell proliferation was associated with an increase in intestinal epithelial cell suppressor of cytokine signaling (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 attributable to GLP-2 activation of the SOCS-3 pathway, which antagonizes the IL-6-mediated increase in STAT-3 signaling.

lamina propria; crypt cell proliferation; interleukin-6; suppressor of cytokine signaling-3; signal transducer and activator of transcription-3