Adenosine A3 receptor agonists inhibit murine macrophage tumor necrosis factor-alpha production in vitro and in vivo

Adenosine and related analogs have been shown to regulate a variety of cell functions through different classes of adenosine receptors. Murine J774.1 macrophage cells were found to predominantly express adenosine A3 receptor RNA relative to adenosine A1 receptor or adenosine A2 receptor RNA. Adenosine receptor agonists, in a dose-dependent manner characteristic of the adenosine A3 receptor, blocked endotoxin-induction of the TNF-alpha gene and TNF-alpha protein expression in the J774.1 macrophage cell line. The adenosine A3 receptor antagonist BW-1433 dose-dependently reversed this adenosine receptor agonist inhibitory effect on TNF-alpha gene expression. Thus, the binding of adenosine receptor agonists to the adenosine A3 receptor interrupts the endotoxin CD14 receptor signal transduction pathway and blocks induction of cytokine TNF-alpha, revealing a novel cross-talk between the murine adenosine A3 receptor and the endotoxin CD14 receptor in J774.1 macrophages.