Abstract
Members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor family of proteins are key modulators of innate immunity regulating inflammation. To date, microbial pathogen-associated molecules and toxins have been identified as key triggers of activation of inflammasomes. However, recently, environmental, and neurodegenerative stimuli have been identified that lead to IL-1β release by means of inflammasomes. IL-1β plays a crucial role during brain inflammation, and caspase-1 appears to be a key modulator of IL-1β bioactivity and the consequent transcriptional regulation of gene expression within the brain during inflammation. We show here that exposure of a human neuroblastoma cell line (SK-N-MC cells) to TNF-α promotes ROS-mediated caspase-1 activation and IL-1β secretion. The involvement of NF-κB in the regulation of IL-1β synthesis is investigated through specific inhibition of this transcription factor. The effect of TNF-α was abolished in the presence of ROS inhibitors as NAC, or DPI. Remarkably, SK-N-MC cells do not respond to ATP stimulation in spite of P2X7R expression. These results provide a mechanism by which danger signals and particulate matter mediate inflammation via the inflammasome in the absence of microbial infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenosine Triphosphate / metabolism
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Apoptosis Regulatory Proteins / metabolism*
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Bacterial Infections / immunology
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Caspase 1 / metabolism
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Cell Line, Tumor
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Enzyme Activation
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Humans
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Immunity, Innate
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Inflammasomes / metabolism*
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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NADPH Oxidases / metabolism
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NF-kappa B / metabolism
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NLR Proteins
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Potassium / metabolism
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Signal Transduction
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Transcriptional Activation / immunology
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Inflammasomes
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Interleukin-1beta
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NF-kappa B
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NLR Proteins
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NLRP1 protein, human
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Tumor Necrosis Factor-alpha
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Adenosine Triphosphate
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NADPH Oxidases
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Caspase 1
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Potassium
Grants and funding
This work was supported in part by grants from Red Temática de Investigación Cooperativa Sanitaria ISCIII (RED RIS) [RD06/0006/0035 and RD06/0006/0021], FIPSE [240800/09], Fondo de Investigación Sanitaria (INTRASALUD 2009) [RD09/0076/00103 and FIS07/0110], Redes Moleculares y Celulares en Enfermedades Inflamatorias Comunidad de Madrid. Consejería de Educación. Convocatoria Cofinanciada con Fondos Estructurales de la Unión Europea (INDISNET S-2011-BMD2332), and DENPEPTHIV, EuroNanoMed (PS09/02669). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.