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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Public Library of Science (PLoS)
2017-01-01
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Online Access: | http://europepmc.org/articles/PMC5266297?pdf=render |
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author | Nynke M Kannegieter Dennis A Hesselink Marjolein Dieterich Rens Kraaijeveld Ajda T Rowshani Pieter J M Leenen Carla C Baan |
author_facet | Nynke M Kannegieter Dennis A Hesselink Marjolein Dieterich Rens Kraaijeveld Ajda T Rowshani Pieter J M Leenen Carla C Baan |
author_sort | Nynke M Kannegieter |
collection | DOAJ |
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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last_indexed | 2024-12-22T03:11:32Z |
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spelling | doaj.art-a3ecb11fa489426b88fb4cee439eb5652022-12-21T18:40:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01121e017080610.1371/journal.pone.0170806The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function.Nynke M KannegieterDennis A HesselinkMarjolein DieterichRens KraaijeveldAjda T RowshaniPieter J M LeenenCarla C BaanMonocytes 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.http://europepmc.org/articles/PMC5266297?pdf=render |
spellingShingle | Nynke M Kannegieter Dennis A Hesselink Marjolein Dieterich Rens Kraaijeveld Ajda T Rowshani Pieter J M Leenen Carla C Baan The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function. PLoS ONE |
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 |
url | http://europepmc.org/articles/PMC5266297?pdf=render |
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