Adenosine A(2b) receptors mediate an increase in interleukin (IL)-6 mRNA and IL-6 protein synthesis in human astroglioma cells

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 A(1) and A(2) 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 A(1)-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 A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine is much less potent. The results indicate that adenosine A2(b) receptors participate in the regulation of the IL-6 gene in astrocytoma cells.