Abstract
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.
Footnotes
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Send reprint requests to: Prof. Dr. Stefan Endres, Division of Clinical Pharmacology, University of Munich, Ziemssenstraße 1, 80336 Munich, Germany. E-mail:Stefan.Endres{at}medinn.med.uni-muenchen.de
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This study was supported by Grant DFG SI 749/2-1 from the Deutsche Forschungsgemeinschaft and by grant of Münchner Medizinischen Wochenschrift e.V. These data are part of the dissertations of Florian Rieder, Stefan Albrich, Christoph Bidlingmaier, and Katrin Wolf (Medizinische Klinik Innenstadt of the Ludwig-Maximilians-University, Munich, in preparation).
- Abbreviations:
- IBD
- inflammatory bowel disease
- TNF
- tumor necrosis factor-α
- IL
- interleukin
- IFNγ
- interferon-γ
- Th1
- T-helper cells type 1
- DSS
- dextran sulfate sodium
- PMA
- phorbol-12-myristate-13-acetate
- LPS
- lipopolysaccharide
- Received July 5, 2000.
- Accepted August 26, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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