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This Article Full Text Full Text (PDF) All Versions of this Article: 293/1/G211    most recent 00530.2006v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Sigalet, D. L. Articles by Sharkey, K. A. Search for Related Content PubMed PubMed Citation Articles by Sigalet, D. L. Articles by Sharkey, K. A.

HORMONES AND SIGNALING

Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2

¹Gastrointestinal Research Group, Institute of Infection, Immunity, and Inflammation, Faculty of Medicine, University of Calgary, Health Science Centre, 3330 Hospital Drive NW, Calgary, AB, Canada; and ²Panum Institute, University of Copenhagen, Copenhagen, Denmark

Submitted 13 November 2006 ; accepted in final form 26 March 2007

Glucagon-like peptide-2 (GLP-2) is an important regulator of nutritional absorptive capacity with anti-inflammatory actions. We hypothesized that GLP-2 reduces intestinal mucosal inflammation by activation of vasoactive intestinal polypeptide (VIP) neurons of the submucosal plexus. Ileitis or colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water. Subsets of animals received (1–33)-GLP-2 (50 µg/kg sc bid) either immediately or 2 days after the establishment of inflammation and were followed for 3–5 days. The involvement of VIP neurons was assessed by concomitant administration of GLP-2 and the VIP antagonist [Lys¹-Pro^2,5-Arg^3,4-Tyr⁶]VIP and by immunohistochemical labeling of GLP-2-activated neurons. In all models, GLP-2 treatment, whether given immediately or delayed until inflammation was established, resulted in significant improvements in animal weights, mucosal inflammation indices (myeloperoxidase levels, histological mucosal scores), and reduced levels of inflammatory cytokines (IFN-, TNF-, IL-1) and inducible nitric oxide synthase, with increased levels of IL-10 in TNBS ileitis and DSS colitis. Reduced rates of crypt cell proliferation and of apoptosis within crypts in inflamed tissues were also noted with GLP-2 treatment. These effects were abolished with coadministration of GLP-2 and the VIP antagonist. GLP-2 was shown to activate neurons and to increase the number of cells expressing VIP in the submucosal plexus of the ileum. These findings suggest that GLP-2 acts as an anti-inflammatory agent through activation of enteric VIP neurons, independent of proliferative effects. They support further studies to examine the role of neural signaling in the regulation of intestinal inflammation.

vasoactive intestinal peptide; trinitrobenzene sulfonic acid colitis; dextran sodium sulfate colitis; Crohn's disease