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Independent signaling pathways in ATP‐evoked secretion of plasminogen and cytokines from microglia

We investigated the action of ATP on the secretion of plasminogen, TNF‐α, and IL‐6 from microglia. ATP (10–100 μM) stimulated the release of plasminogen from rat cultured microglia in a concentration‐dependent manner with a peak response at 5–10 min after the stimulation. The release was dependent on extracellular Ca2+ and was blocked by pretreatment with oxidized ATP, a blocker of P2X7. UTP, an agonist of P2Y2, also stimulated the release of plasminogen from a subpopulation (about 20% of total cells) of cultured microglia. The release was also dependent on extracellular Ca2+, suggesting a role of stocker‐operated calcium entry (SOC). ATP potently stimulated TNF‐α release from 2 h after the stimulation with TNF‐α mRNA expression in primary cultures of rat brain microglia. The TNF‐α release was maximally elicited by 1 mM ATP and 2′‐ and 3′‐O‐(4‐benzoylbenzoyl)‐adenosine 5′‐triphosphate (BzATP), a P2X7 selective agonist, suggesting the involvement of P2X7. This TNF‐α release was correlated with a sustained Ca2+ influx. The release was inhibited by PD98059, an inhibitor of MEK1 which activates extracellular signal‐regulated protein kinase (ERK), and SB203580, an inhibitor of p38 MAP kinase. However, both ERK and p38 were rapidly activated by ATP even in the absence of extracellular Ca2+. These results indicate that extracellular ATP triggers TNF‐α release in rat microglia via P2X7 in a manner dependent on the sustained Ca2+ influx and via the ERK/p38 cascade independently of Ca2+ influx. ATP caused the mRNA expression and release of IL‐6 in a concentration‐dependent manner in MG‐5. The physiological meaning of these independent release mechanisms is also discussed. Drug Dev. Res. 53:166–171, 2001. © 2001 Wiley‐Liss, Inc.