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VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity

The inflammasome is a specialized multiprotein oligomer that regulates IL-1β production. Although regulation of the inflammasome is related to crucial inflammatory disorders such as sepsis, pharmacological inhibitors that effectively inhibit inflammasome activity are limited. Here, we evaluated the...

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Autores principales: Lee, Sung Kyun, Kim, Ye Seon, Bae, Geon Ho, Lee, Ha Young, Bae, Yoe-Sik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778193/
https://www.ncbi.nlm.nih.gov/pubmed/31586128
http://dx.doi.org/10.1038/s41598-019-50806-9
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author Lee, Sung Kyun
Kim, Ye Seon
Bae, Geon Ho
Lee, Ha Young
Bae, Yoe-Sik
author_facet Lee, Sung Kyun
Kim, Ye Seon
Bae, Geon Ho
Lee, Ha Young
Bae, Yoe-Sik
author_sort Lee, Sung Kyun
collection PubMed
description The inflammasome is a specialized multiprotein oligomer that regulates IL-1β production. Although regulation of the inflammasome is related to crucial inflammatory disorders such as sepsis, pharmacological inhibitors that effectively inhibit inflammasome activity are limited. Here, we evaluated the effects of a phospholipase D1 (PLD1)-selective inhibitor (VU0155069) against sepsis and inflammasome activation. VU0155069 strongly enhances survival rate in cecal ligation and puncture (CLP)-induced sepsis by inhibiting lung inflammation, leukocyte apoptosis, and the production of proinflammatory cytokines, especially IL-1β. VU0155069 also significantly blocked IL-1β production, caspase-1 activation, and pyroptosis caused by several inflammasome-activating signals in the bone marrow-derived macrophages (BMDMs). However, VU0155069 did not affect LPS-induced activation of signaling molecules such as MAPK, Akt, NF-κB, and NLRP3 expression in the BMDMs. VU0155069 also failed to affect mitochondrial ROS generation and calcium increase caused by nigericin or ATP, and subsequent ASC oligomerization caused by several inflammasome-activating signals. VU0155069 indirectly inhibited caspase-1 activity caused by LPS + nigericin in BMDMs independent of PLD1 activity. We demonstrated that a PLD1 inhibitor, VU0155069, shows anti-septic activity as well as inflammasome-inhibiting effects. Our results suggest that VU0155069 can be considered a novel inflammasome inhibitor.
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spelling pubmed-67781932019-10-09 VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity Lee, Sung Kyun Kim, Ye Seon Bae, Geon Ho Lee, Ha Young Bae, Yoe-Sik Sci Rep Article The inflammasome is a specialized multiprotein oligomer that regulates IL-1β production. Although regulation of the inflammasome is related to crucial inflammatory disorders such as sepsis, pharmacological inhibitors that effectively inhibit inflammasome activity are limited. Here, we evaluated the effects of a phospholipase D1 (PLD1)-selective inhibitor (VU0155069) against sepsis and inflammasome activation. VU0155069 strongly enhances survival rate in cecal ligation and puncture (CLP)-induced sepsis by inhibiting lung inflammation, leukocyte apoptosis, and the production of proinflammatory cytokines, especially IL-1β. VU0155069 also significantly blocked IL-1β production, caspase-1 activation, and pyroptosis caused by several inflammasome-activating signals in the bone marrow-derived macrophages (BMDMs). However, VU0155069 did not affect LPS-induced activation of signaling molecules such as MAPK, Akt, NF-κB, and NLRP3 expression in the BMDMs. VU0155069 also failed to affect mitochondrial ROS generation and calcium increase caused by nigericin or ATP, and subsequent ASC oligomerization caused by several inflammasome-activating signals. VU0155069 indirectly inhibited caspase-1 activity caused by LPS + nigericin in BMDMs independent of PLD1 activity. We demonstrated that a PLD1 inhibitor, VU0155069, shows anti-septic activity as well as inflammasome-inhibiting effects. Our results suggest that VU0155069 can be considered a novel inflammasome inhibitor. Nature Publishing Group UK 2019-10-04 /pmc/articles/PMC6778193/ /pubmed/31586128 http://dx.doi.org/10.1038/s41598-019-50806-9 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lee, Sung Kyun
Kim, Ye Seon
Bae, Geon Ho
Lee, Ha Young
Bae, Yoe-Sik
VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity
title VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity
title_full VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity
title_fullStr VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity
title_full_unstemmed VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity
title_short VU0155069 inhibits inflammasome activation independent of phospholipase D1 activity
title_sort vu0155069 inhibits inflammasome activation independent of phospholipase d1 activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778193/
https://www.ncbi.nlm.nih.gov/pubmed/31586128
http://dx.doi.org/10.1038/s41598-019-50806-9
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