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The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function

Monocytes and macrophages play key roles in many disease states, including cellular and humoral rejection after solid organ transplantation (SOT). To suppress alloimmunity after SOT, immunosuppressive drug therapy is necessary. However, little is known about the effects of the immunosuppressive drug...

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Autores principales: Kannegieter, Nynke M., Hesselink, Dennis A., Dieterich, Marjolein, Kraaijeveld, Rens, Rowshani, Ajda T., Leenen, Pieter J. M., Baan, Carla C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266297/
https://www.ncbi.nlm.nih.gov/pubmed/28122021
http://dx.doi.org/10.1371/journal.pone.0170806
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author Kannegieter, Nynke M.
Hesselink, Dennis A.
Dieterich, Marjolein
Kraaijeveld, Rens
Rowshani, Ajda T.
Leenen, Pieter J. M.
Baan, Carla C.
author_facet Kannegieter, Nynke M.
Hesselink, Dennis A.
Dieterich, Marjolein
Kraaijeveld, Rens
Rowshani, Ajda T.
Leenen, Pieter J. M.
Baan, Carla C.
author_sort Kannegieter, Nynke M.
collection PubMed
description Monocytes and macrophages play key roles in many disease states, including cellular and humoral rejection after solid organ transplantation (SOT). To suppress alloimmunity after SOT, immunosuppressive drug therapy is necessary. However, little is known about the effects of the immunosuppressive drugs tacrolimus and mycophenolic acid (MPA) on monocyte activation and function. Here, the effect of these immunosuppressants on monocytes was investigated by measuring phosphorylation of three intracellular signaling proteins which all have a major role in monocyte function: p38MAPK, ERK and Akt. In addition, biological functions downstream of these signaling pathways were studied, including cytokine production, phagocytosis and differentiation into macrophages. To this end, blood samples from healthy volunteers were spiked with diverse concentrations of tacrolimus and MPA. Tacrolimus (200 ng/ml) inhibited phosphorylation of p38MAPK by 30% (mean) in CD14+ monocytes which was significantly less than in activated CD3+ T cells (max 60%; p < 0.05). This immunosuppressive agent also partly inhibited p-AKT (14%). MPA, at a therapeutic concentration showed the strongest effect on p-AKT (27% inhibition). p-ERK was inhibited with a maximum of 15% after spiking with either tacrolimus or MPA. The production of IL-1β and phagocytosis by monocytes were not affected by tacrolimus concentrations, whereas MPA did inhibit IL-1β production by 50%. Monocyte/macrophage polarization was shifted to an M2-like phenotype in the presence of tacrolimus, while MPA increased the expression of M2 surface markers, including CD163 and CD200R, on M1 macrophages. These results show that tacrolimus and MPA do not strongly affect monocyte function, apart from a change in macrophage polarization, to a clinically relevant degree.
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spelling pubmed-52662972017-02-17 The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function Kannegieter, Nynke M. Hesselink, Dennis A. Dieterich, Marjolein Kraaijeveld, Rens Rowshani, Ajda T. Leenen, Pieter J. M. Baan, Carla C. PLoS One Research Article Monocytes and macrophages play key roles in many disease states, including cellular and humoral rejection after solid organ transplantation (SOT). To suppress alloimmunity after SOT, immunosuppressive drug therapy is necessary. However, little is known about the effects of the immunosuppressive drugs tacrolimus and mycophenolic acid (MPA) on monocyte activation and function. Here, the effect of these immunosuppressants on monocytes was investigated by measuring phosphorylation of three intracellular signaling proteins which all have a major role in monocyte function: p38MAPK, ERK and Akt. In addition, biological functions downstream of these signaling pathways were studied, including cytokine production, phagocytosis and differentiation into macrophages. To this end, blood samples from healthy volunteers were spiked with diverse concentrations of tacrolimus and MPA. Tacrolimus (200 ng/ml) inhibited phosphorylation of p38MAPK by 30% (mean) in CD14+ monocytes which was significantly less than in activated CD3+ T cells (max 60%; p < 0.05). This immunosuppressive agent also partly inhibited p-AKT (14%). MPA, at a therapeutic concentration showed the strongest effect on p-AKT (27% inhibition). p-ERK was inhibited with a maximum of 15% after spiking with either tacrolimus or MPA. The production of IL-1β and phagocytosis by monocytes were not affected by tacrolimus concentrations, whereas MPA did inhibit IL-1β production by 50%. Monocyte/macrophage polarization was shifted to an M2-like phenotype in the presence of tacrolimus, while MPA increased the expression of M2 surface markers, including CD163 and CD200R, on M1 macrophages. These results show that tacrolimus and MPA do not strongly affect monocyte function, apart from a change in macrophage polarization, to a clinically relevant degree. Public Library of Science 2017-01-25 /pmc/articles/PMC5266297/ /pubmed/28122021 http://dx.doi.org/10.1371/journal.pone.0170806 Text en © 2017 Kannegieter et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Kannegieter, Nynke M.
Hesselink, Dennis A.
Dieterich, Marjolein
Kraaijeveld, Rens
Rowshani, Ajda T.
Leenen, Pieter J. M.
Baan, Carla C.
The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function
title The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function
title_full The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function
title_fullStr The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function
title_full_unstemmed The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function
title_short The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function
title_sort effect of tacrolimus and mycophenolic acid on cd14+ monocyte activation and function
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266297/
https://www.ncbi.nlm.nih.gov/pubmed/28122021
http://dx.doi.org/10.1371/journal.pone.0170806
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