Abstract
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.
Highlights
Interleukin-1 is a pro-inflammatory cytokine that mediates part of the host defense response to injury and infection
We have investigated the role of P2X7 receptor and of an associated calcium-activated potassium conductance (BK channels) in IL-1 maturation and releasing processes by Schwann cells
In searching for a link between the P2X7 receptor and the activation of IL-1-converting enzyme (ICE), we found that enhancing potassium efflux from Schwann cells upregulated the production of IL-1, while strongly reducing potassium efflux led to opposite effects
Summary
Interleukin-1 is a pro-inflammatory cytokine that mediates part of the host defense response to injury and infection. Perregaux and Gabel [15] were first to demonstrate that nigericin, a potassium ionophore, or ATP potentiated greatly the release of IL-1 from LPS-primed macrophages Since this pioneer work, in vitro and in vivo studies [16, 17] have shown that extracellular ATP acting on the P2X7 receptor, an ionotropic receptor that plays a pivotal role in the modulation of immune and inflammatory responses [9], was a very potent agent to stimulate the production of large quantities of extracellular mature IL-1. A specific feature of P2X7 receptors expressed by cultured mouse Schwann cells are there association with a calcium-activated potassium conductance and a chloride conductance [26] This intriguing phenotype makes the study of P2X7 receptors expressed by Schwann cells interesting as the different conductances activated by extracellular ATP could participate to an integrated regulation of inflammatory processes occuring in the peripheral nervous system
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