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(Journal of Leukocyte Biology. 2000;68:97-103.)
© 2000 by Society for Leukocyte Biology

Suppression of TNF- production in human mononuclear cells by an adenosine kinase inhibitor

Division of Clinical Pharmacology, Medizinische Klinik, Klinikum Innenstadt, University of Munich, Germany; and
^* Division of Rheumatology, University of California, San Diego School of Medicine, La Jolla

Correspondence: Stefan Endres, M.D., Clinical Pharmacology, Medizinische Klinik, University of Munich, Ziemssenstrasse 1, 80336 München, Germany. E-mail: EndresS{at}lrz.uni-muenchen.de

Adenosine exerts potent anti-inflammatory activities through inhibition of cytokine synthesis by activated monocytes. Adenosine is rapidly phosphorylated intracellularly by adenosine kinase. GP515, an adenosine kinase inhibitor, prevents the phosphorylation of adenosine to AMP and thereby locally enhances the adenosine concentration. GP515 has exhibited significant anti-inflammatory effects in several murine models of inflammation. In this study we investigated the effect of GP515 alone and in combination with exogenous adenosine or with rolipram, a phosphodiesterase inhibitor, on tumor necrosis factor (TNF-) synthesis in human peripheral blood mononuclear cells (PBMC) or whole blood. Lipopolysaccharide (LPS; 10 ng/mL)-stimulated PBMC were incubated in the absence or presence of these substances. GP515 alone showed a dose-dependent suppression of TNF- production with an IC₅₀ of 80 µM. The TNF--inhibiting effects of adenosine and GP515 were reversed in the presence of the cAMP antagonist (Rp)-cAMPS, supporting the hypothesis of a cAMP-mediated pathway. Combinations of GP515 with either adenosine or rolipram led to an additive inhibition of TNF- synthesis. These experiments are the first to demonstrate efficacy of an adenosine kinase inhibitor in TNF- suppression in cells of human origin. The findings form a basis to investigate these strategies in animal models of TNF--mediated chronic inflammatory diseases.

Key Words: cytokines • lipopolysaccharide • second messengers

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