The cytokine interleukin (IL)‐6 has recently been demonstrated to play a role in the pathology of Alzheimer's disease (AD). The mechanisms leading to increased IL‐6 levels in brains of AD patients are still unknown. Because in experimental animals ischemia increases both the level of cytokines and the extracellular concentrations of adenosine in the brain, we hypothesized that these two phenomena may be functionally connected and that adenosine might increase IL‐6 gene expression in the brain. Here we show that the mixed A₁ and A₂ agonist 5′‐(N‐ethylcarboxamido)adenosine (NECA) induces an increase in IL‐6 mRNA levels and protein synthesis in the human astrocytoma cell line U373 MG. The A₁‐specific agonists R‐phenylisopropyladenosine and cyclopentyladenosine are much less potent, and the A_2a‐specific agonist CGS‐21680 shows only marginal effects. Increased levels of mRNA are already found within 30 min after NECA treatment. The A_2a‐selective antagonists 8‐(3‐chlorostyryl)caffeine and KF17837 [(E)‐8‐(3,4‐dimethoxystyryl)‐1,3‐dipropyl‐7‐methylxanthine], which have also some antagonistic properties at A_2b receptors, and the nonspecific adenosine antagonist 8‐phenyltheophylline were equipotent at inhibiting the NECA‐induced increase in IL‐6 protein synthesis, whereas the specific A₁ antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine is much less potent. The results indicate that adenosine A_2b receptors participate in the regulation of the IL‐6 gene in astrocytoma cells.