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...

Full description

Bibliographic Details
Main Authors: Nynke M Kannegieter, Dennis A Hesselink, Marjolein Dieterich, Rens Kraaijeveld, Ajda T Rowshani, Pieter J M Leenen, Carla C Baan
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2017-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC5266297?pdf=render
_version_ 1819108538855718912
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.
first_indexed 2024-12-22T03:11:32Z
format Article
id doaj.art-a3ecb11fa489426b88fb4cee439eb565
institution Directory Open Access Journal
issn 1932-6203
language English
last_indexed 2024-12-22T03:11:32Z
publishDate 2017-01-01
publisher Public Library of Science (PLoS)
record_format Article
series PLoS ONE
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
work_keys_str_mv AT nynkemkannegieter theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT dennisahesselink theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT marjoleindieterich theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT renskraaijeveld theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT ajdatrowshani theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT pieterjmleenen theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT carlacbaan theeffectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT nynkemkannegieter effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT dennisahesselink effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT marjoleindieterich effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT renskraaijeveld effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT ajdatrowshani effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT pieterjmleenen effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction
AT carlacbaan effectoftacrolimusandmycophenolicacidoncd14monocyteactivationandfunction