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Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism
The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis pla...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454555/ https://www.ncbi.nlm.nih.gov/pubmed/37628747 http://dx.doi.org/10.3390/ijms241612571 |
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author | Adorni, Maria Pia Papotti, Bianca Borghi, Maria Orietta Raschi, Elena Zimetti, Francesca Bernini, Franco Meroni, Pier Luigi Ronda, Nicoletta |
author_facet | Adorni, Maria Pia Papotti, Bianca Borghi, Maria Orietta Raschi, Elena Zimetti, Francesca Bernini, Franco Meroni, Pier Luigi Ronda, Nicoletta |
author_sort | Adorni, Maria Pia |
collection | PubMed |
description | The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations. |
format | Online Article Text |
id | pubmed-10454555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-104545552023-08-26 Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism Adorni, Maria Pia Papotti, Bianca Borghi, Maria Orietta Raschi, Elena Zimetti, Francesca Bernini, Franco Meroni, Pier Luigi Ronda, Nicoletta Int J Mol Sci Article The impact of JAK/STAT inhibitors, which are used in various inflammatory diseases, on cardiovascular risk is controversial and has recently raised safety concerns. Our study investigates the direct effects of tofacitinib on macrophage cholesterol metabolism, which is crucial for atherosclerosis plaque development and stability. Cultured human macrophages THP-1 were used to assess the impact of tofacitinib on cell cholesterol efflux and synthesis via radioisotopic methods, and on cholesterol uptake by measuring the cell cholesterol content with a fluorometric assay. The cholesterol acceptors and donors were either standard lipoproteins or sera from patients with juvenile idiopathic arthritis (JIA) and from control subjects. Tofacitinib significantly increased the macrophage cholesterol efflux to all acceptors; it reduced cholesterol uptake from both the normal and hypercholesterolemic sera; and it reduced cholesterol synthesis. The treatment of macrophages with tofacitinib was able to increase the cholesterol efflux and decrease cholesterol uptake when using sera from untreated JIA patients with active disease as cholesterol acceptors and donors, respectively. In conclusion, our in vitro data support the concept that tofacitinib has a favorable impact on macrophage cholesterol metabolism, even in the presence of sera from rheumatologic patients, and suggest that other mechanisms may be responsible for the cardiovascular risk associated with tofacitinib use in selected patient populations. MDPI 2023-08-08 /pmc/articles/PMC10454555/ /pubmed/37628747 http://dx.doi.org/10.3390/ijms241612571 Text en © 2023 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 Adorni, Maria Pia Papotti, Bianca Borghi, Maria Orietta Raschi, Elena Zimetti, Francesca Bernini, Franco Meroni, Pier Luigi Ronda, Nicoletta Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism |
title | Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism |
title_full | Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism |
title_fullStr | Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism |
title_full_unstemmed | Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism |
title_short | Effect of the JAK/STAT Inhibitor Tofacitinib on Macrophage Cholesterol Metabolism |
title_sort | effect of the jak/stat inhibitor tofacitinib on macrophage cholesterol metabolism |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10454555/ https://www.ncbi.nlm.nih.gov/pubmed/37628747 http://dx.doi.org/10.3390/ijms241612571 |
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