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

Autor: Andreas Eigler, S. Endres, Simon Erhardt, David L. Boyle, Gunther Hartmann, Verena Matschke, Gary S. Firestein
Rok vydání: 2000
Předmět:
Zdroj: Journal of Leukocyte Biology. 68:97-103
ISSN: 1938-3673
0741-5400
DOI: 10.1189/jlb.68.1.97
Popis: 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 α (TNF-α) 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-α production with an IC50 of 80 μM. The TNF-α-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-α synthesis. These experiments are the first to demonstrate efficacy of an adenosine kinase inhibitor in TNF-α suppression in cells of human origin. The findings form a basis to investigate these strategies in animal models of TNF-α-mediated chronic inflammatory diseases.
Databáze: OpenAIRE
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