TNF-Α may mediate inflammasome activation in the absence of bacterial infection in more than one way.
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.
Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Susana
S
Álvarez
Ma Ángeles
MÁ
Muñoz-Fernández
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001424:Bacterial Infections / Q000276:immunology; D020170:Caspase 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000070576:NLR Proteins; D011188:Potassium / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D016328:NF-kappa B; D000070576:NLR Proteins; C427903:NLRP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; D020170:Caspase 1; D011188:Potassium