Lysophosphatidylcholine stimulates IL-1beta release from microglia via a P2X7 receptor-independent mechanism.
IL-1beta 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-1beta 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-1beta. Neither LPC-induced IL-1beta release nor LPC-stimulated intracellular Ca(2+) increases were affected by inhibition of P2X(7) ATP receptors with oxidized ATP. Microglial LPC-induced IL-1beta release was suppressed in Ca(2+)-free medium or during inhibition of nonselective cation channels with Gd(3+) or La(3+). It was also attenuated when Ca(2+)-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-1beta release, demonstrating the importance of membrane hyperpolarization. Furthermore, LPC-stimulated caspase activity was unaffected by Ca(2+)-free medium or CTX, suggesting that secretion but not processing of IL-1beta is Ca(2+)- and voltage-dependent. In summary, these data indicate that the activity of nonselective cation channels and Ca(2+)-activated K(+) channels is required for optimal IL-1beta release from LPC-stimulated microglia.
Stock
Christian
C
Institute of Physiology II, University of Muenster, Muenster, Germany.
Schilling
Tom
T
Schwab
Albrecht
A
Eder
Claudia
C
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism / Q000502:physiology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008564:Membrane Potentials; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7
D015220:Calcium Channels; D053583:Interleukin-1beta; D007473:Ion Channels; D008244:Lysophosphatidylcholines; C546469:P2rx7 protein, mouse; D015221:Potassium Channels; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D002118:Calcium