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Volume 17, Number 9, Issue of May 1, 1997 pp. 2939-2946
Copyright ©1997 Society for Neuroscience

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

Received Jan. 2, 1997; revised Feb. 5, 1997; accepted Feb. 10, 1997.

Nephi Stella^{1, 2}, Angeles Estellés¹, Julio Siciliano¹, Martine Tencé¹, Solange Desagher¹, Daniele Piomelli², Jacques Glowinski¹, and Joël Prémont¹

¹ Laboratoire de Neuropharmacologie, Institut National de la Santé et de la Recherche Médicale U114, Collège de France, 75231 Paris Cedex 05, France, and ² The Neurosciences Institute, San Diego, California 92121

During neuropathological states associated with inflammation, the levels of cytokines such as interleukin-1 (IL-1) are increased. Several studies have suggested that the neuronal damage observed in pathogenesis implicating IL-1 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-1 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 (cPLA₂, an enzyme that mediates AA release). Indeed, P_2Y2 antisense oligonucleotides reduce the ATP-evoked release of AA only from IL-1-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-1. We also report evidence indicating that the coupling of newly expressed P_2Y2 receptors to cPLA₂ is dependent on PKC activity. These results suggest that during inflammatory conditions, IL-1 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.

Key words: purinoceptor; phospholipase; cytokine; inflammation; glutamate; neurotoxicity

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