Lysophosphatidylcholine stimulates IL-1β release from microglia via a P2X7 receptor-independent mechanism

IL-1 beta 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 beta release from activated microglia (brain macrophages) that occurred independently of P2X(7) ATP receptor activation. Stimulation of LPS-preactivated microglia with lysophosphatidylcholine (LPC) caused rapid processing and secretion of mature 17-kDa IL-1 beta. Neither LPC-induced IL-1 beta release nor LPC-stimulated intracellular Ca2+ increases were affected by inhibition of P2X(7) ATP receptors with oxidized ATP. Microglial LPC-induced IL-1 beta 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 beta 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 beta 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 beta release from LPC-stimulated microglia.