PMID:18490713

Citation	Pelegrin, P, Barroso-Gutierrez, C and Surprenant, A (2008) P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophage. J. Immunol. 180:7147-57
Abstract	The proinflammatory IL-1 cytokines IL-1alpha, IL-1beta, and IL-18 are key mediators of the acute immune response to injury and infection. Mechanisms underlying their cellular release remain unclear. Activation of purinergic P2X(7) receptors (P2X(7)R) by extracellular ATP is a key physiological inducer of rapid IL-1beta release from LPS-primed macrophage. We investigated patterns of ATP-mediated release of IL-1 cytokines from three macrophage types in attempts to provide direct evidence for or against distinct release mechanisms. We used peritoneal macrophage from P2X(7)R(-/-) mice and found that release of IL-1alpha, IL-18, as well as IL-1beta, by ATP resulted exclusively from activation of P2X(7)R, release of all these IL-1 cytokines involved pannexin-1 (panx1), and that there was both a panx1-dependent and -independent component to IL-1beta release. We compared IL-1-release patterns from LPS-primed peritoneal macrophage, RAW264.7 macrophage, and J774A.1 macrophage. We found RAW264.7 macrophage readily release pro-IL-1beta independently of panx1 but do not release mature IL-1beta because they do not express apoptotic speck-like protein with a caspase-activating recruiting domain and so have no caspase-1 inflammasome activity. We delineated two distinct release pathways: the well-known caspase-1 cascade mediating release of processed IL-1beta that was selectively blocked by inhibition of caspase-1 or panx1, and a calcium-independent, caspase-1/panx1-independent release of pro-IL-1beta that was selectively blocked by glycine. None of these release responses were associated with cell damage or cytolytic effects. This provides the first direct demonstration of a distinct signaling mechanism responsible for ATP-induced release of pro-IL-1beta.
Links	PubMed
Keywords	Adenosine Triphosphate/metabolism; Animals; Caspase 1/metabolism; Cell Death; Cell Line; Connexins/immunology; Connexins/metabolism; Cytoskeletal Proteins/immunology; Cytoskeletal Proteins/metabolism; Interleukin-18/immunology; Interleukin-18/metabolism; Interleukin-1alpha/immunology; Interleukin-1alpha/metabolism; Interleukin-1beta/immunology; Interleukin-1beta/metabolism; Lipopolysaccharides/immunology; Macrophages/immunology; Macrophages/metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins/immunology; Nerve Tissue Proteins/metabolism; Receptors, Purinergic P2/metabolism; Receptors, Purinergic P2X7
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