Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-κB-driven protein synthesis. J Immunol

Department of Pathology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
The Journal of Immunology (Impact Factor: 5.36). 01/2006; 175(11):7611-22. DOI: 10.4049/jimmunol.175.11.7611
Source: PubMed

ABSTRACT The proinflammatory cytokines IL-1beta and IL-18 are inactive until cleaved by the enzyme caspase-1. Stimulation of the P2X7 receptor (P2X7R), an ATP-gated ion channel, triggers rapid activation of caspase-1. In this study we demonstrate that pretreatment of primary and Bac1 murine macrophages with TLR agonists is required for caspase-1 activation by P2X7R but it is not required for activation of the receptor itself. Caspase-1 activation by nigericin, a K+/H+ ionophore, similarly requires LPS priming. This priming by LPS is dependent on protein synthesis, given that cyclohexamide blocks the ability of LPS to prime macrophages for activation of caspase-1 by the P2X7R. This protein synthesis is likely mediated by NF-kappaB, as pretreatment of cells with the proteasome inhibitor MG132, or the IkappaB kinase inhibitor Bay 11-7085 before LPS stimulation blocks the ability of LPS to potentiate the activation of caspase-1 by the P2X7R. Thus, caspase-1 regulation in macrophages requires inflammatory stimuli that signal through the TLRs to up-regulate gene products required for activation of the caspase-1 processing machinery in response to K+-releasing stimuli such as ATP.

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Available from: George R Dubyak, Nov 02, 2014
    • "Inflammasome priming normally occurs downstream of the transcription factor NF-B (Bauernfeind et al., 2009) and essentially involves trans-activation of the various genes that encode the different inflammasome subunits and their cytokine targets. Stimuli known to lead to inflammasome priming include toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS), cytokines such as tumour necrosis factor (TNF), and reactive oxygen species (Bauernfeind et al., 2011; Bauernfeind et al., 2009; Kahlenberg et al., 2005). "
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    • "A well-characterized route linking TLRs with the NLRP3 inflammasome is via an ATP-gated purinergic receptor, P2X 7 (Mariathasan et al., 2006) which we have previously shown to be expressed and functional in cord blood mononuclear cells (CBMCs) (Warren et al., 2008). While TLR4 leads to increased synthesis of mRNA for the precursor form of IL- 1β, processing to its mature and releasable form is reliant upon the exit of K + from cells—a role performed by the P2X 7 receptor (Kahlenberg et al., 2005). Thus, while numerous studies have shown links between TLR4 and LPS to cytokine release, stimulation with ATP increases IL-1β release further through the P2X 7 -receptor and may be a missing ingredient in understanding sPTB. "
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