Interleukin-1 Enhances the ATP-Evoked Release of Arachidonic Acid from Mouse Astrocytes

Abstract

During neuropathological states associated with inflammation, the levels of cytokines such as interleukin-1β (IL-1β) are increased. Several studies have suggested that the neuronal damage observed in pathogenesis implicating IL-1β are caused by an alteration in the neurochemical interactions between neurons and astrocytes. We report here that treating striatal astrocytes in primary culture with IL-1β for 22–24 hr enhances the ATP-evoked release of arachidonic acid (AA) with no effect on the ATP-induced accumulation of inositol phosphates. The molecular mechanism responsible for this effect involves the expression of P 2Y2 receptors (a subtype of purinoceptor activated by ATP) and cytosolic phospholipase A2 (cPLA 2, an enzyme that mediates AA release). Indeed, P 2Y2 antisense oligonucleotides reduce the ATP-evoked release of AA only from IL-1β-treated astrocytes. Further, both the amount of cPLA2 (as assessed by Western blotting) and the release of AA resulting from direct activation of cPLA 2 increased fourfold in cells treated with IL-1β. We also report evidence indicating that the coupling of newly expressed P 2Y2 receptors to cPLA 2 is dependent on PKC activity. These results suggest that during inflammatory conditions, IL-1β reveals a functional P 2Y2 signaling pathway in astrocytes that results in a dramatic increase in the levels of free AA. This pathway may thus contribute to the neuronal loss associated with cerebral ischemia or traumatic brain injury.