Regulation of arachidonic acid mobilization in lipopolysaccharide-activated P388D1 macrophages by adenosine triphosphate

Murine P388D, macrophages exhibit a delayed prostaglandin biosynthetic response when exposed to bacterial lipopolysaccharide (LPS) for prolonged periods of time that is dependent on induction of the genes coding for Group V secretory phospholipase A(2) and cyclooxygenase-2, We herein report that LPS-induced arachidonic acid (AA) metabolite release in P388D(1) macrophages is strongly attenuated by the P2X(7) purinergic receptor antagonists periodate-oxidized ATP and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, and this is accompanied by suppression of the expression of both Group V secretory phospholipase A(2) and cyclooxygenase-2, The effect appears to be specific for LPS, because the P2X(7) purinergic receptor antagonists do not affect P388D, cell stimulation by other stimuli such as platelet-activating factor or the Ca2+ ionophore A23187. Moreover, extracellular nucleotides are found to stimulate macrophage AA mobilization with a pharmacological profile that implicates the participation of the P2X(7) receptor and that is inhibited by periodate-oxidized ATP. Collectively these results demonstrate coupling of the P2X(7) receptor to the AA cascade in P388D, macrophages and implicate the participation of this type of receptor in LPS-induced AA mobilization.