Adenosine Kinase Inhibitor GP515 Improves Experimental Colitis in Mice

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 296; no. 1; p. 99
• Main Authors: Siegmund, B, Rieder, F, Albrich, S, Wolf, K, Bidlingmaier, C, Firestein, G S, Boyle, D, Lehr, H A, Loher, F, Hartmann, G, Endres, S, Eigler, A
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.01.2001
• Subjects: Adenosine Kinase - antagonists & inhibitors; Animals; Antigens, CD - biosynthesis; Antigens, Differentiation, T-Lymphocyte - biosynthesis; Cells, Cultured; Colitis - chemically induced; Colitis - drug therapy; Colitis - pathology; Colon - metabolism; Colon - pathology; Dextran Sulfate; Enzyme Inhibitors - therapeutic use; Female; Flow Cytometry; Gastrointestinal Agents - therapeutic use; Interferon-gamma - biosynthesis; Lectins, C-Type; Mice; Mice, Inbred BALB C; Organ Size; Ribonucleosides - therapeutic use; Spleen - pathology; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 0022-3565; 1521-0103

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-γ (IFNγ) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNγ concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNγ synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNγ synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.