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Vol. 296, Issue 1, 99-105, January 2001
Division of Clinical Pharmacology, Medizinische Klinik Innenstadt
of the Ludwig-Maximilians-University, Munich, Germany (B.S., F.R.,
S.A., K.W., C.B., F.L., G.H., S.E., A.E.); Division of Rheumatology,
University of California San Diego School of Medicine, La Jolla,
California (G.S.F., D.B.); and Institute of Pathology, University of
Mainz, Mainz, Germany (H-A.L.)
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-
(IFN) 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 IFN concentration in the colonic tissue.
Third, spleen weight was reduced in GP515-treated DSS mice. And fourth,
IFN 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 IFN synthesis and CD69 expression. Adenosine
kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.
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