Cargando…
GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes
Toll-like receptors (TLR) are crucial sensors of microbial agents such as bacterial or viral compounds. These receptors constitute key players in the induction of inflammation, e.g. in septic or chronic inflammatory diseases. Colony-stimulating factors (CSFs) such as granulocyte-macrophage-CSF (GM-C...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047522/ https://www.ncbi.nlm.nih.gov/pubmed/27695085 http://dx.doi.org/10.1371/journal.pone.0162667 |
_version_ | 1782457430035136512 |
---|---|
author | Sadeghi, Kambis Wisgrill, Lukas Wessely, Isabelle Diesner, Susanne C. Schüller, Simone Dürr, Celia Heinle, Armando Sachet, Monika Pollak, Arnold Förster-Waldl, Elisabeth Spittler, Andreas |
author_facet | Sadeghi, Kambis Wisgrill, Lukas Wessely, Isabelle Diesner, Susanne C. Schüller, Simone Dürr, Celia Heinle, Armando Sachet, Monika Pollak, Arnold Förster-Waldl, Elisabeth Spittler, Andreas |
author_sort | Sadeghi, Kambis |
collection | PubMed |
description | Toll-like receptors (TLR) are crucial sensors of microbial agents such as bacterial or viral compounds. These receptors constitute key players in the induction of inflammation, e.g. in septic or chronic inflammatory diseases. Colony-stimulating factors (CSFs) such as granulocyte-macrophage-CSF (GM-CSF) or granulocyte-CSF (G-CSF) have been extensively investigated in their capacity to promote myelopoiesis in febrile neutropenia or to overcome immunosuppression in patients suffering from sepsis-associated neutropenia or from monocytic immunoincompetence. We report here that GM-CSF, downregulates TLR1, TLR2 and TLR4 in a time- and dose-dependent fashion in human monocytes. Diminished pathogen recognition receptor expression was accompanied by reduced downstream p38 and extracellular-signal-regulated kinase (ERK) signaling upon lipoteichoic acid (LTA) and lipopolysaccharide (LPS) binding—and accordingly led to impaired proinflammatory cytokine production. Knockdown experiments of the transcription factors PU.1 and VentX showed that GM-CSF driven effects on TLR regulation is entirely PU.1 but not VentX dependent. We further analysed monocyte TLR and CD14 expression upon exposure to the IMID® immunomodulatory drug Pomalidomide (CC-4047), a Thalidomide analogue known to downregulate PU.1. Indeed, Pomalidomide in part reversed the GM-CSF-mediated effects. Our data indicate a critical role of PU.1 in the regulation of TLR1, 2, 4 and of CD14, thus targeting PU.1 ultimately results in TLR modulation. The PU.1 mediated immunomodulatory properties of GM-CSF should be taken into consideration upon usage of GM-CSF in inflammatory or infection-related conditions. |
format | Online Article Text |
id | pubmed-5047522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50475222016-10-27 GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes Sadeghi, Kambis Wisgrill, Lukas Wessely, Isabelle Diesner, Susanne C. Schüller, Simone Dürr, Celia Heinle, Armando Sachet, Monika Pollak, Arnold Förster-Waldl, Elisabeth Spittler, Andreas PLoS One Research Article Toll-like receptors (TLR) are crucial sensors of microbial agents such as bacterial or viral compounds. These receptors constitute key players in the induction of inflammation, e.g. in septic or chronic inflammatory diseases. Colony-stimulating factors (CSFs) such as granulocyte-macrophage-CSF (GM-CSF) or granulocyte-CSF (G-CSF) have been extensively investigated in their capacity to promote myelopoiesis in febrile neutropenia or to overcome immunosuppression in patients suffering from sepsis-associated neutropenia or from monocytic immunoincompetence. We report here that GM-CSF, downregulates TLR1, TLR2 and TLR4 in a time- and dose-dependent fashion in human monocytes. Diminished pathogen recognition receptor expression was accompanied by reduced downstream p38 and extracellular-signal-regulated kinase (ERK) signaling upon lipoteichoic acid (LTA) and lipopolysaccharide (LPS) binding—and accordingly led to impaired proinflammatory cytokine production. Knockdown experiments of the transcription factors PU.1 and VentX showed that GM-CSF driven effects on TLR regulation is entirely PU.1 but not VentX dependent. We further analysed monocyte TLR and CD14 expression upon exposure to the IMID® immunomodulatory drug Pomalidomide (CC-4047), a Thalidomide analogue known to downregulate PU.1. Indeed, Pomalidomide in part reversed the GM-CSF-mediated effects. Our data indicate a critical role of PU.1 in the regulation of TLR1, 2, 4 and of CD14, thus targeting PU.1 ultimately results in TLR modulation. The PU.1 mediated immunomodulatory properties of GM-CSF should be taken into consideration upon usage of GM-CSF in inflammatory or infection-related conditions. Public Library of Science 2016-10-03 /pmc/articles/PMC5047522/ /pubmed/27695085 http://dx.doi.org/10.1371/journal.pone.0162667 Text en © 2016 Sadeghi 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 Sadeghi, Kambis Wisgrill, Lukas Wessely, Isabelle Diesner, Susanne C. Schüller, Simone Dürr, Celia Heinle, Armando Sachet, Monika Pollak, Arnold Förster-Waldl, Elisabeth Spittler, Andreas GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes |
title | GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes |
title_full | GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes |
title_fullStr | GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes |
title_full_unstemmed | GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes |
title_short | GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes |
title_sort | gm-csf down-regulates tlr expression via the transcription factor pu.1 in human monocytes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047522/ https://www.ncbi.nlm.nih.gov/pubmed/27695085 http://dx.doi.org/10.1371/journal.pone.0162667 |
work_keys_str_mv | AT sadeghikambis gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT wisgrilllukas gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT wesselyisabelle gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT diesnersusannec gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT schullersimone gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT durrcelia gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT heinlearmando gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT sachetmonika gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT pollakarnold gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT forsterwaldlelisabeth gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT spittlerandreas gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes |