Activation of adenosine A3 receptors on macrophages inhibits tumor necrosis factor-α

Murine macrophage-derived tumor necrosis factor alpha (TNF-α) gene expression has been shown to be dramatically induced by bacterial lipopolysaccharide, and to be dependent upon nuclear factor-κB (NF-κB) binding sites in its promoter for the lipopolysaccharide induction. Murine J774.1 macrophage cells were found to predominately express the 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 the endotoxin induction of the TNF-α gene and TNF-α protein expression in the J774.1 macrophage cell line. The adenosine A₃ receptor antagonist BW-1433 dose-dependently reversed this adenosine inhibitory effect on TNF-α 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-α, revealing a novel cross-talk between the murine adenosine A₃ receptor and the endotoxin CD14 receptor in J774.1 macrophages.