Interleukin-1 enhances the ATP-evoked release of arachidonic acid from mouse astrocytes.
During neuropathological states associated with inflammation, the levels of cytokines such as interleukin-1beta (IL-1beta) are increased. Several studies have suggested that the neuronal damage observed in pathogenesis implicating IL-1beta 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-1beta 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 P2Y2 receptors (a subtype of purinoceptor activated by ATP) and cytosolic phospholipase A2 (cPLA2, an enzyme that mediates AA release). Indeed, P2Y2 antisense oligonucleotides reduce the ATP-evoked release of AA only from IL-1beta-treated astrocytes. Further, both the amount of cPLA2 (as assessed by Western blotting) and the release of AA resulting from direct activation of cPLA2 increased fourfold in cells treated with IL-1beta. We also report evidence indicating that the coupling of newly expressed P2Y2 receptors to cPLA2 is dependent on PKC activity. These results suggest that during inflammatory conditions, IL-1beta reveals a functional P2Y2 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.
Stella
N
N
Laboratoire de Neuropharmacologie, Institut National de la Santé et de la Recherche Médicale U114, Collège de France, 75231 Paris Cedex 05, France.
Estellés
A
A
Siciliano
J
J
Tencé
M
M
Desagher
S
S
Piomelli
D
D
Glowinski
J
J
Prémont
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice
D001095:Arachidonic Acids; D007375:Interleukin-1; D000255:Adenosine Triphosphate