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Lysophosphatidylcholine Stimulates IL-1 Release from Microglia via a P2X₇ Receptor-Independent Mechanism¹

Christian Stock^2,*, Tom Schilling^2,, Albrecht Schwab^* and Claudia Eder^3,

^* Institute of Physiology II, University of Muenster, Muenster, Germany, and Institute of Physiology, Medical Faculty Charité, Berlin, Germany

IL-1 released from activated macrophages contributes significantly to tissue damage in inflammatory, degenerative, and autoimmune diseases. In the present study, we identified a novel mechanism of IL-1 release from activated microglia (brain macrophages) that occurred independently of P2X₇ ATP receptor activation. Stimulation of LPS-preactivated microglia with lysophosphatidylcholine (LPC) caused rapid processing and secretion of mature 17-kDa IL-1. Neither LPC-induced IL-1 release nor LPC-stimulated intracellular Ca²⁺ increases were affected by inhibition of P2X₇ ATP receptors with oxidized ATP. Microglial LPC-induced IL-1 release was suppressed in Ca²⁺-free medium or during inhibition of nonselective cation channels with Gd³⁺ or La³⁺. It was also attenuated when Ca²⁺-activated K⁺ channels were blocked with charybdotoxin (CTX). The electroneutral K⁺ ionophore nigericin did not reverse the suppressive effects of CTX on LPC-stimulated IL-1 release, demonstrating the importance of membrane hyperpolarization. Furthermore, LPC-stimulated caspase activity was unaffected by Ca²⁺-free medium or CTX, suggesting that secretion but not processing of IL-1 is Ca²⁺- and voltage-dependent. In summary, these data indicate that the activity of nonselective cation channels and Ca²⁺-activated K⁺ channels is required for optimal IL-1 release from LPC-stimulated microglia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) Grant SFB 507/C7 (to C.E.) and Grant Schw 407/9-2 (to A.S.). C.E. is a recipient of a Heisenberg Fellowship.

² C.S. and T.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Claudia Eder, Institute of Physiology, Medical Faculty Charité, Tucholskystrasse 2, D-10117 Berlin, Germany. E-mail address: claudia.eder{at}charite.de

⁴ Abbreviations used in this paper: LPC, lysophosphatidylcholine; CTX, charybdotoxin; ICE, IL-1-converting enzyme; MTX, margatoxin; oATP, oxidized ATP; [Ca²⁺]_i, intracellular Ca²⁺ concentration.

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