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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...

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Autores principales: Adorni, Maria Pia, Papotti, Bianca, Borghi, Maria Orietta, Raschi, Elena, Zimetti, Francesca, Bernini, Franco, Meroni, Pier Luigi, Ronda, Nicoletta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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