It has previously demonstrated that adenine (6-amino-6H-purine) exhibited a vasoactive effect in contracted aorta. The adenine receptor (AdeR) has recently been identified as a G protein coupled purinergic receptor in diverse organs. It has been suggested that adenine acts as a signaling molecule through the activation of AdeR. The present study investigated the effect of adenine on endotoxin-stimulated mouse macrophages (RAW 264.7 cells) and focused on the AdeR signaling pathway. RAW 264.7 cells were treated with adenine and stimulated with lipopolysaccharide (LPS, Toll-like receptor 4 agonist) from Escherichia coli. Adenine inhibited tumor necrosis factor (TNF)-α secretion in RAW 264.7 cells. The inhibition by adenine was significantly attenuated in the presence of either adenyl cyclase (AC) or protein kinase A (PKA) inhibitors. Furthermore, adenine restored AdeR gene expression. These results firstly demonstrated that adenine acts as an anti-endotoxin compounds through a AdeR/AC/PKA signaling cascade.
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