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Ricin Toxin Activates the NALP3 Inflammasome
Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a resul...
Autores principales: | , , |
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Formato: | Texto |
Lenguaje: | English |
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MDPI
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2942780/ https://www.ncbi.nlm.nih.gov/pubmed/20862209 http://dx.doi.org/10.3390/toxins2061500 |
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author | Lindauer, Meghan Wong, John Magun, Bruce |
author_facet | Lindauer, Meghan Wong, John Magun, Bruce |
author_sort | Lindauer, Meghan |
collection | PubMed |
description | Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result of the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We reported previously that macrophages and interleukin-1β (IL-1β) signaling are required for murine host immune responses to ricin delivered to the lungs. Here we report that ricin-mediated IL-1β release from bone-marrow derived macrophages is dependent on the NALP3 inflammasome, a scaffolding complex that mediates pro-IL-1β cleavage to active IL-1β by caspase-1. Release of IL-1β from macrophages was suppressed by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and high extracellular K(+), which are two agents known to inhibit NALP3/cryopyrin/CIAS1 inflammasome formation. By employing inhibitors of p38 MAPK and JNK, we demonstrated that ricin-mediated release of IL-1β was enhanced, rather than suppressed, by inhibition of SAPK phosphorylation. In contrast, proteasomal inhibitors bortezomib and MG-132 completely suppressed ricin-induced IL-1β release from macrophages. These data suggest that ricin-mediated translational inhibition itself, by fostering the disappearance of labile protein(s) that normally suppress inflammasome formation, may constitute the mechanism underlying IL-1-dependent inflammatory signaling by ricin. |
format | Text |
id | pubmed-2942780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-29427802010-09-20 Ricin Toxin Activates the NALP3 Inflammasome Lindauer, Meghan Wong, John Magun, Bruce Toxins (Basel) Article Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result of the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We reported previously that macrophages and interleukin-1β (IL-1β) signaling are required for murine host immune responses to ricin delivered to the lungs. Here we report that ricin-mediated IL-1β release from bone-marrow derived macrophages is dependent on the NALP3 inflammasome, a scaffolding complex that mediates pro-IL-1β cleavage to active IL-1β by caspase-1. Release of IL-1β from macrophages was suppressed by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and high extracellular K(+), which are two agents known to inhibit NALP3/cryopyrin/CIAS1 inflammasome formation. By employing inhibitors of p38 MAPK and JNK, we demonstrated that ricin-mediated release of IL-1β was enhanced, rather than suppressed, by inhibition of SAPK phosphorylation. In contrast, proteasomal inhibitors bortezomib and MG-132 completely suppressed ricin-induced IL-1β release from macrophages. These data suggest that ricin-mediated translational inhibition itself, by fostering the disappearance of labile protein(s) that normally suppress inflammasome formation, may constitute the mechanism underlying IL-1-dependent inflammatory signaling by ricin. MDPI 2010-06-17 /pmc/articles/PMC2942780/ /pubmed/20862209 http://dx.doi.org/10.3390/toxins2061500 Text en © 2010 by the authors; licensee MDPI, Basel, Switzerland http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Article Lindauer, Meghan Wong, John Magun, Bruce Ricin Toxin Activates the NALP3 Inflammasome |
title | Ricin Toxin Activates the NALP3 Inflammasome |
title_full | Ricin Toxin Activates the NALP3 Inflammasome |
title_fullStr | Ricin Toxin Activates the NALP3 Inflammasome |
title_full_unstemmed | Ricin Toxin Activates the NALP3 Inflammasome |
title_short | Ricin Toxin Activates the NALP3 Inflammasome |
title_sort | ricin toxin activates the nalp3 inflammasome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2942780/ https://www.ncbi.nlm.nih.gov/pubmed/20862209 http://dx.doi.org/10.3390/toxins2061500 |
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