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TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells
Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1β. We have previously shown that the inhib...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125426/ https://www.ncbi.nlm.nih.gov/pubmed/34062977 http://dx.doi.org/10.3390/ijms22094875 |
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author | Ranta-aho, Sofia Piippo, Niina Korhonen, Eveliina Kaarniranta, Kai Hytti, Maria Kauppinen, Anu |
author_facet | Ranta-aho, Sofia Piippo, Niina Korhonen, Eveliina Kaarniranta, Kai Hytti, Maria Kauppinen, Anu |
author_sort | Ranta-aho, Sofia |
collection | PubMed |
description | Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1β. We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. In that study, we used a well-known Hsp90 inhibitor geldanamycin, but it cannot be used as a therapy due to its adverse effects, including ocular toxicity. Here, we have tested the effects of a novel Hsp90 inhibitor, TAS-116, on NLRP3 activation using geldanamycin as a reference compound. Using our existing protocol, inflammasome activation was induced in IL-1α-primed ARPE-19 cells with the proteasome and autophagy inhibitors MG-132 and bafilomycin A1, respectively. Intracellular caspase-1 activity was determined using a commercial caspase-1 activity kit and the FLICA assay. The levels of IL-1β were measured from cell culture medium samples by ELISA. Cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and lactate dehydrogenase (LDH) measurements. Our findings show that TAS-116 could prevent the activation of caspase-1, subsequently reducing the release of mature IL-1β. TAS-116 has a better in vitro therapeutic index than geldanamycin. In summary, TAS-116 appears to be a well-tolerated Hsp90 inhibitor, with the capability to prevent the activation of the NLRP3 inflammasome in human RPE cells. |
format | Online Article Text |
id | pubmed-8125426 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81254262021-05-17 TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells Ranta-aho, Sofia Piippo, Niina Korhonen, Eveliina Kaarniranta, Kai Hytti, Maria Kauppinen, Anu Int J Mol Sci Article Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1β. We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. In that study, we used a well-known Hsp90 inhibitor geldanamycin, but it cannot be used as a therapy due to its adverse effects, including ocular toxicity. Here, we have tested the effects of a novel Hsp90 inhibitor, TAS-116, on NLRP3 activation using geldanamycin as a reference compound. Using our existing protocol, inflammasome activation was induced in IL-1α-primed ARPE-19 cells with the proteasome and autophagy inhibitors MG-132 and bafilomycin A1, respectively. Intracellular caspase-1 activity was determined using a commercial caspase-1 activity kit and the FLICA assay. The levels of IL-1β were measured from cell culture medium samples by ELISA. Cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and lactate dehydrogenase (LDH) measurements. Our findings show that TAS-116 could prevent the activation of caspase-1, subsequently reducing the release of mature IL-1β. TAS-116 has a better in vitro therapeutic index than geldanamycin. In summary, TAS-116 appears to be a well-tolerated Hsp90 inhibitor, with the capability to prevent the activation of the NLRP3 inflammasome in human RPE cells. MDPI 2021-05-05 /pmc/articles/PMC8125426/ /pubmed/34062977 http://dx.doi.org/10.3390/ijms22094875 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ranta-aho, Sofia Piippo, Niina Korhonen, Eveliina Kaarniranta, Kai Hytti, Maria Kauppinen, Anu TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells |
title | TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells |
title_full | TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells |
title_fullStr | TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells |
title_full_unstemmed | TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells |
title_short | TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells |
title_sort | tas-116, a well-tolerated hsp90 inhibitor, prevents the activation of the nlrp3 inflammasome in human retinal pigment epithelial cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125426/ https://www.ncbi.nlm.nih.gov/pubmed/34062977 http://dx.doi.org/10.3390/ijms22094875 |
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