Maturation and release of interleukin-1beta by lipopolysaccharide-primed mouse Schwann cells require the stimulation of P2X7 receptors.
The P2X7 receptor, mainly expressed by immune cells, is a ionotropic receptor activated by high concentration of extracellular ATP. It is involved in several processes relevant to immunomodulation and inflammation. Among these processes, the production of extracellular interleukin-1beta (IL-1beta), a pro-inflammatory cytokine, plays a major role in the activation of the cytokine network. We have investigated the role of P2X7 receptor and of an associated calcium-activated potassium conductance (BK channels) in IL-1beta maturation and releasing processes by Schwann cells. Lipopolysaccharide-primed Schwann cells synthesized large amounts of pro-IL-1beta but did not release detectable amounts of pro or mature IL-1beta. ATP on its own had no effect on the synthesis of pro-IL-1beta, but a co-treatment with lipopolysaccharide and ATP led to the maturation and the release of IL-1beta by Schwann cells. Both mechanisms were blocked by oxidized ATP. IL-1beta-converting enzyme (ICE), the caspase responsible for the maturation of pro-IL-1beta in IL-1beta, was activated by P2X7 receptor stimulation. The specific inhibition of ICE by the caspase inhibitor Ac-Tyr-Val-Ala-Asp-aldehyde blocked the maturation of IL-1beta. In searching for a link between the P2X7 receptor and the activation of ICE, we found that enhancing potassium efflux from Schwann cells upregulated the production of IL-1beta, while strongly reducing potassium efflux led to opposite effects. Blocking BK channels actually modulated IL-1beta release. Taken together, these results show that P2X7 receptor stimulation and associated BK channels, through the activation of ICE, leads to the maturation and the release of IL-1beta by immune-challenged Schwann cells.
Colomar
Aurore
A
Département de Physiologie, Centre de Recherches en Sciences Neurologiques, Université de Montréal, Montréal H3C 3J7, Canada.
Marty
Vincent
V
Médina
Chantal
C
Combe
Chantal
C
Parnet
Patricia
P
Amédée
Thierry
T
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D015870:Gene Expression / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D015213:Neuroimmunomodulation / Q000502:physiology; D009924:Organ Culture Techniques; D011188:Potassium / Q000493:pharmacokinetics; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051193:Toll-Like Receptors
D007375:Interleukin-1; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C546469:P2rx7 protein, mouse; D024681:Potassium Channels, Calcium-Activated; D011498:Protein Precursors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D051193:Toll-Like Receptors; C043830:interleukin 1 precursor; D000255:Adenosine Triphosphate; D020170:Caspase 1; D011188:Potassium