Enteric neural pathways mediate the anti-inflammatory actions of glucagon-like peptide 2.
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 mug/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 [Lys(1)-Pro(2,5)-Arg(3,4)-Tyr(6)]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-gamma, TNF-alpha, IL-1beta) 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.
Sigalet
David L
DL
Gastrointestinal Research Group, Institute of Infection, Immunity, and Inflammation, Faculty of Medicine, University of Calgary, Health Science Centre, 3330 Hospital Drive NW, Calgary, Alberta, Canada. sigalet@ucalgary.ca
Wallace
Laurie E
LE
Holst
Jens J
JJ
Martin
Gary R
GR
Kaji
Tatsuru
T
Tanaka
Hiroaki
H
Sharkey
Keith A
KA
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000502:physiology*; D053767:Glucagon-Like Peptide 2 / Q000502:physiology* / Q000627:therapeutic use; D007079:Ileitis / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009496:Neurotensin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014302:Trinitrobenzenesulfonic Acid; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D053767:Glucagon-Like Peptide 2; D011993:Recombinant Fusion Proteins; C069189:(VIP-neurotensin) hybrid antagonist; D014660:Vasoactive Intestinal Peptide; D009496:Neurotensin; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate