Activation of adenosine A(3) receptors on macrophages inhibits tumor necrosis factor-alpha

Murine macrophage-derived tumor necrosis factor alpha (TNF-alpha) gene expression has been shown to be dramatically induced by bacterial lipopolysaccharide, and to be dependent upon nuclear factor-kappa B (NF-kappa B) binding sites in its promoter for the lipopolysaccharide induction. Murine J774.1 macrophage cells were found to predominately express the adenosine A(3) receptor RNA relative to adenosine A(1) receptor or adenosine A(2) receptor RNA. Adenosine receptor agonists, in a dose-dependent manner characteristic of the adenosine A(3) receptor, blocked the endotoxin induction of the TNF-alpha gene and TNF-alpha protein expression in the J774.1 macrophage cell line. The adenosine A(3) receptor antagonist BW-1433 dose-dependently reversed this adenosine inhibitory effect on TNF-alpha gene expression. Thus, the binding of adenosine receptor agonists to the adenosine A(3) 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 A(3) receptor and the endotoxin CD14 receptor in J774.1 macrophages.