Tacrolimus inhibits NF-κB activation in peripheral human T cells.

The calcineurin inhibitor, tacrolimus (TAC), inhibits the protein phosphatase activity of calcineurin, leading to suppression of the nuclear translocation of NFAT and inhibition of T cell activation. Apart from NFAT also the transcription factor NF-κB plays a key functional role in T cell activation...

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Autores principales:	Ramin Vafadari, Rens Kraaijeveld, Willem Weimar, Carla C Baan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/57f414828d1f4c9eab023345d215f9eb
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spelling	oai:doaj.org-article:57f414828d1f4c9eab023345d215f9eb2021-11-18T07:51:09ZTacrolimus inhibits NF-κB activation in peripheral human T cells.1932-620310.1371/journal.pone.0060784https://doaj.org/article/57f414828d1f4c9eab023345d215f9eb2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23573283/?tool=EBIhttps://doaj.org/toc/1932-6203The calcineurin inhibitor, tacrolimus (TAC), inhibits the protein phosphatase activity of calcineurin, leading to suppression of the nuclear translocation of NFAT and inhibition of T cell activation. Apart from NFAT also the transcription factor NF-κB plays a key functional role in T cell activation. Therefore, blockade of the NF-κB activation cascade by immunosuppressive drugs prevents immune activation. Here we studied whether TAC blocks NF-κB activation in peripheral human T cells. After anti-CD3/CD28-activation of T cells from healthy volunteers, NF-κB (p65) phosphorylation was measured by flow cytometry in CD3+ T cells, CD4+ helper T cells and CD8+ cytotoxic T cells in the absence and presence of TAC 10 ng/mL, sotrastaurin 500 nM (positive control) and mycophenolic acid 10 µg/mL (negative control; n = 6). NF-κB transcriptional activity was measured by ELISA and intracellular TNFα protein, a downstream target, was measured by flow cytometry to assess the functional consequences of NF-κB blockade. Anti-CD3/28-activation induced NF-κB phosphorylation in CD3+ T cells, CD4+ T cells and CD8+ T cells by 34% (mean), 38% and 30% resp. (p<0.01). Sotrastaurin inhibited NF-κB activation in the respective T cell subsets by 93%, 95% and 86% (p<0.01 vs. no drug), while mycophenolic acid did not affect this activation pathway. Surprisingly, TAC also inhibited NF-κB phosphorylation, by 55% (p<0.01) in CD3+ T cells, by 56% (p<0.01) in CD4+ T cells and by 51% in CD8+ T cells (p<0.01). In addition, TAC suppressed NF-κB DNA binding capacity by 55% (p<0.05) in CD3+ T cells and TNFα protein expression was inhibited in CD3+ T cells, CD4+ T cells and CD8+ T cells by 76%, 71% and 93% resp. (p<0.01 vs. no drug), confirming impaired NF-κB signaling. This study shows the suppressive effect of TAC on NF-κB signaling in peripheral human T cell subsets, measured at three specific positions in the NF-κB activation cascade.Ramin VafadariRens KraaijeveldWillem WeimarCarla C BaanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e60784 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ramin Vafadari Rens Kraaijeveld Willem Weimar Carla C Baan Tacrolimus inhibits NF-κB activation in peripheral human T cells.
description	The calcineurin inhibitor, tacrolimus (TAC), inhibits the protein phosphatase activity of calcineurin, leading to suppression of the nuclear translocation of NFAT and inhibition of T cell activation. Apart from NFAT also the transcription factor NF-κB plays a key functional role in T cell activation. Therefore, blockade of the NF-κB activation cascade by immunosuppressive drugs prevents immune activation. Here we studied whether TAC blocks NF-κB activation in peripheral human T cells. After anti-CD3/CD28-activation of T cells from healthy volunteers, NF-κB (p65) phosphorylation was measured by flow cytometry in CD3+ T cells, CD4+ helper T cells and CD8+ cytotoxic T cells in the absence and presence of TAC 10 ng/mL, sotrastaurin 500 nM (positive control) and mycophenolic acid 10 µg/mL (negative control; n = 6). NF-κB transcriptional activity was measured by ELISA and intracellular TNFα protein, a downstream target, was measured by flow cytometry to assess the functional consequences of NF-κB blockade. Anti-CD3/28-activation induced NF-κB phosphorylation in CD3+ T cells, CD4+ T cells and CD8+ T cells by 34% (mean), 38% and 30% resp. (p<0.01). Sotrastaurin inhibited NF-κB activation in the respective T cell subsets by 93%, 95% and 86% (p<0.01 vs. no drug), while mycophenolic acid did not affect this activation pathway. Surprisingly, TAC also inhibited NF-κB phosphorylation, by 55% (p<0.01) in CD3+ T cells, by 56% (p<0.01) in CD4+ T cells and by 51% in CD8+ T cells (p<0.01). In addition, TAC suppressed NF-κB DNA binding capacity by 55% (p<0.05) in CD3+ T cells and TNFα protein expression was inhibited in CD3+ T cells, CD4+ T cells and CD8+ T cells by 76%, 71% and 93% resp. (p<0.01 vs. no drug), confirming impaired NF-κB signaling. This study shows the suppressive effect of TAC on NF-κB signaling in peripheral human T cell subsets, measured at three specific positions in the NF-κB activation cascade.
format	article
author	Ramin Vafadari Rens Kraaijeveld Willem Weimar Carla C Baan
author_facet	Ramin Vafadari Rens Kraaijeveld Willem Weimar Carla C Baan
author_sort	Ramin Vafadari
title	Tacrolimus inhibits NF-κB activation in peripheral human T cells.
title_short	Tacrolimus inhibits NF-κB activation in peripheral human T cells.
title_full	Tacrolimus inhibits NF-κB activation in peripheral human T cells.
title_fullStr	Tacrolimus inhibits NF-κB activation in peripheral human T cells.
title_full_unstemmed	Tacrolimus inhibits NF-κB activation in peripheral human T cells.
title_sort	tacrolimus inhibits nf-κb activation in peripheral human t cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/57f414828d1f4c9eab023345d215f9eb
work_keys_str_mv	AT raminvafadari tacrolimusinhibitsnfkbactivationinperipheralhumantcells AT renskraaijeveld tacrolimusinhibitsnfkbactivationinperipheralhumantcells AT willemweimar tacrolimusinhibitsnfkbactivationinperipheralhumantcells AT carlacbaan tacrolimusinhibitsnfkbactivationinperipheralhumantcells
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Tacrolimus inhibits NF-κB activation in peripheral human T cells.

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