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...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5047522?pdf=render |
| _version_ | 1811208829064445952 |
|---|---|
| author | Kambis Sadeghi Lukas Wisgrill Isabelle Wessely Susanne C Diesner Simone Schüller Celia Dürr Armando Heinle Monika Sachet Arnold Pollak Elisabeth Förster-Waldl Andreas Spittler |
| author_facet | Kambis Sadeghi Lukas Wisgrill Isabelle Wessely Susanne C Diesner Simone Schüller Celia Dürr Armando Heinle Monika Sachet Arnold Pollak Elisabeth Förster-Waldl Andreas Spittler |
| author_sort | Kambis Sadeghi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T04:28:18Z |
| format | Article |
| id | doaj.art-cbc9e68743e54f46be292766c6bc3973 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T04:28:18Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-cbc9e68743e54f46be292766c6bc39732022-12-22T03:48:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-011110e016266710.1371/journal.pone.0162667GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes.Kambis SadeghiLukas WisgrillIsabelle WesselySusanne C DiesnerSimone SchüllerCelia DürrArmando HeinleMonika SachetArnold PollakElisabeth Förster-WaldlAndreas SpittlerToll-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.http://europepmc.org/articles/PMC5047522?pdf=render |
| spellingShingle | Kambis Sadeghi Lukas Wisgrill Isabelle Wessely Susanne C Diesner Simone Schüller Celia Dürr Armando Heinle Monika Sachet Arnold Pollak Elisabeth Förster-Waldl Andreas Spittler GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human Monocytes. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC5047522?pdf=render |
| work_keys_str_mv | AT kambissadeghi gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT lukaswisgrill gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT isabellewessely gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT susannecdiesner gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT simoneschuller gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT celiadurr gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT armandoheinle gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT monikasachet gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT arnoldpollak gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT elisabethforsterwaldl gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes AT andreasspittler gmcsfdownregulatestlrexpressionviathetranscriptionfactorpu1inhumanmonocytes |