Glucagon-Like Peptide-2 and Common Therapeutics in a Murine Model of Ulcerative Colitis
- Departments of Physiology (M.-C.L'H., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada
- Address correspondence to:
Dr. Patricia L. Brubaker, Department of Physiology, University of Toronto, Medical Sciences Building, Room 3366, 1 King's College Circle, Toronto, Ontario, M5S 1A8, Canada. E-mail: p.brubaker{at}utoronto.ca
Abstract
The intestinal hormone glucagon-like peptide-2 (GLP-2) enhances bowel growth and reduces the severity of colonic injury in dextran sulfate sodium (DSS)-induced colitis in mice. In humans, ulcerative colitis is normally treated with aminosalicylates (ASAs) and corticosteroids (CSs) to reduce inflammation. However, whether the intestinotropic effects of GLP-2 are altered when combined with ASAs and/or CSs has not previously been explored. Thus, each agent [vehicle, ASA (sulfasalazine), CS (methylprednisolone), and ASA + CS] was administered alone or with GLP-2 to normal mice or mice with 3.5% DSS in the drinking water, for 10 consecutive days. GLP-2 treatment of DSS-mice increased survival and small intestinal weight (p < 0.05), and decreased body weight loss and colonic damage (p < 0.05). Furthermore, GLP-2 increased the number of proliferating cells in the colonic crypts of DSS-mice (p < 0.05). Administration of ASA, CS, or ASA + CS alone did not affect growth of the intestine in DSS-mice. However, administration of GLP-2 in combination with ASA was permissive for the beneficial effects of GLP-2 on survival and colonic damage, whereas CS treatment prevented these effects of GLP-2. Concomitant administration of GLP-2 with ASA + CS resulted in intermediate effects. No differences between colonic myeloperoxidase activity or IκB levels (an inhibitor of the nuclear factor-κB pro-inflammatory pathway) were found for any of these therapeutic agents. When taken together, the ability of GLP-2 to protect colonic mucosal architecture in DSS-colitis, and its effectiveness when given in combination with ASA, but not with CS, suggests a novel approach for the treatment of patients with colitis.
Footnotes
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This work was supported by operating grants from the Canadian Institutes of Health Research and the Crohn's and Colitis Foundation of Canada. M.C.L'H. is a recipient of Doctoral Research Studentships from the Canadian Institutes of Health Research, the Ontario Graduate Scholarship, and the Department of Physiology, University of Toronto; and P.L.B. is supported by the Canada Research Chair program. This work was presented in a poster format at the Digestive Disease Week of the American Gastroenterological Association, May 19–22, 2002, San Francisco, CA.
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DOI: 10.1124/jpet.103.051771.
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ABBREVIATIONS: GLP-2, glucagon-like peptide-2; EGF, epidermal growth factor; TGF-α, transforming growth factor-α; DSS, dextran sulfate sodium; ASA, aminosalicylic acid (aminosalicylate); CS, corticosteroid; UC, ulcerative colitis; NF-κB, nuclear factor-κB; PBS, phosphate-buffered saline; MPO, myeloperoxidase; PCNA, proliferating cell nuclear antigen; CDS, colonic damage score; IκB, inhibitor of NF-κB; ANOVA, analysis of variance.
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- Received March 17, 2003.
- Accepted April 15, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
