Cyclosporin A and FK506 decrease adenosine kinase activity and adenosine uptake in T-lymphocytes.
Adenosine is a potent modulator of immune function, and adenosine kinase (AK), a rate-limiting enzyme for adenosine uptake and metabolism, is a potential mediator of adenosine regulation. We have found that adenosine uptake increased six- to 18-fold during T-lymphocyte activation. This increase correlated with an increase in AK activity but not in AK protein. The immunosuppressive drugs cyclosporin A (CsA) and FK506 inhibited both adenosine uptake and AK activity in a concentration-dependent manner. Among several nucleosides and bases, the inhibition of uptake was selective for adenosine. Immunosuppressive drug treatment also caused a twofold increase in the level of extracellular adenosine but not of inosine, suggesting that the effect is not related to the general toxicity of drugs. Inhibitors of calcineurin did not inhibit adenosine uptake, suggesting that this protein phosphatase does not mediate the effect. These data demonstrate that CsA and FK506 enhance adenosine concentrations in T-lymphocytes by way of a mechanism that involves AK inhibition.
Spychala
Jozef
J
Departments of Pharmacology and Internal Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. jozek@med.unc.edu
Mitchell
Beverly S
BS
D000241:Adenosine / Q000096:biosynthesis / Q000493:pharmacokinetics; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D016559:Tacrolimus / Q000494:pharmacology*; D013936:Thymidine / Q000493:pharmacokinetics; D014316:Tritium
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D014316:Tritium; D016572:Cyclosporine; D000248:Adenosine Kinase; D000241:Adenosine; D013936:Thymidine; D016559:Tacrolimus