Adenosine induces hemeoxygenase-1 expression in microglia through the activation of phosphatidylinositol 3-kinase and nuclear factor E2-related factor 2

Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti‐inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase‐1 (HO‐1). The H2O2‐induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3–6 h, compared with that in untreated cells. Adenosine induced HO‐1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2‐related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3‐kinase (PI3K) and Akt pathways appear to mediate HO‐1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO‐1 promoter activity in an ARE‐dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine‐induced HO‐1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO‐1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. © 2008 Wiley‐Liss, Inc.