ADENOSINE A(2B) RECEPTORS MEDIATE AN INCREASE IN INTERLEUKIN (IL)-6 MESSENGER-RNA 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 l eading to increased IL-6 levels in brains of AD patients are still unk nown. Because in experimental animals ischemia increases both the leve l of cytokines and the extracellular concentrations of adenosine in th e brain, we hypothesized that these two phenomena may be functionally connected and that adenosine might increase IL-6 gene expression in th e brain. Here we show that the mixed A(1) and A(2) agonist 5'-(N-ethyl carboxamido)adenosine (NECA) induces an increase in IL-6 mRNA levels a nd protein synthesis in the human astrocytoma cell line U373 MG. The A (1)-specific agonists R-phenylisopropyladenosine and cyclopentyladenos ine are much less potent, and the A(2a)-specific agonist CGS-21680 sho ws only marginal effects. Increased levels of mRNA are already found w ithin 30 min after NECA treatment. The A(2a)-selective antagonists 8-( 3-chlorostyryl)caffeine and KF17837 4-dimethoxystyryl)-1,3-dipropyl-7- methylxanthine], which have also some antagonistic properties at A(2b) receptors, and the nonspecific adenosine antagonist 8-phenyltheophyll ine were equipotent at inhibiting the NECA-induced increase in IL-6 pr otein synthesis, whereas the specific A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine is much less potent. The results indicate that aden osine A2(b) receptors participate in the regulation of the IL-6 gene i n astrocytoma cells.