SurprenantJImmunol2008

SurprenantJImmunol2008 - P2X 7 Receptor Differentially...

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Unformatted text preview: P2X 7 Receptor Differentially Couples to Distinct Release Pathways for IL-1 b in Mouse Macrophage 1 Pablo Pelegrin,* Consuelo Barroso-Gutierrez, † and Annmarie Surprenant 2 * The proinflammatory IL-1 cytokines IL-1 a , IL-1 b , 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-1 b 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 2 / 2 mice and found that release of IL-1 a , IL-18, as well as IL-1 b , 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-1 b 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-1 b independently of panx1 but do not release mature IL-1 b 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-1 b that was selectively blocked by inhi- bition of caspase-1 or panx1, and a calcium-independent, caspase-1/panx1-independent release of pro-IL-1 b 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-1 b . The Journal of Im- munology, 2008, 180: 7147–7157. T he IL-1 family of cytokines comprises 11 members whose aberrant production leads to chronic inflammation. IL-1 a , IL-1 b , IL-1Ra, and, more recently, IL-18, have been the most studied of the IL-1 cytokines (1, 2). The synthesis, process- ing, and secretion of the proinflammatory IL-1 cytokines, IL-1 a , IL-1 b , and IL-18 are tightly regulated by several mechanisms (3). Although much is now known about the biosynthesis and post- translational processing of these cytokines (3–8), much remains unknown about their secretion. TLR engagement by inflammatory stimuli, such as LPS and other bacterial endotoxins, leads to cel- lular accumulation of these cytokines mainly via activation of NF- k B- and/or MAPK-signaling cascades. Intracellular IL-1 b and IL-18 are synthesized as inactive proforms that are processed by activated caspase-1 to produce the active, mature forms. In con- trast, IL-1 a , which is bioactive in its unprocessed state, can also be posttranslationally processed by the calcium-dependent protease,...
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SurprenantJImmunol2008 - P2X 7 Receptor Differentially...

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