PMID- 27695085
OWN - NLM
STAT- MEDLINE
DCOM- 20170614
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 10
DP  - 2016
TI  - GM-CSF Down-Regulates TLR Expression via the Transcription Factor PU.1 in Human 
      Monocytes.
PG  - e0162667
LID - 10.1371/journal.pone.0162667 [doi]
LID - e0162667
AB  - 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(R) 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.
FAU - Sadeghi, Kambis
AU  - Sadeghi K
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Wisgrill, Lukas
AU  - Wisgrill L
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Wessely, Isabelle
AU  - Wessely I
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Diesner, Susanne C
AU  - Diesner SC
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Schuller, Simone
AU  - Schuller S
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Durr, Celia
AU  - Durr C
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Heinle, Armando
AU  - Heinle A
AD  - Dept. of Surgery, Medical University of Vienna, Vienna, Austria.
FAU - Sachet, Monika
AU  - Sachet M
AD  - Dept. of Surgery, Medical University of Vienna, Vienna, Austria.
FAU - Pollak, Arnold
AU  - Pollak A
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Forster-Waldl, Elisabeth
AU  - Forster-Waldl E
AD  - Dept. of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric 
      Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria.
FAU - Spittler, Andreas
AU  - Spittler A
AD  - Core Facility Flow Cytometry, Medical University of Vienna, Vienna, Austria.
LA  - eng
PT  - Journal Article
DEP - 20161003
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharide Receptors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (TLR2 protein, human)
RN  - 0 (TLR4 protein, human)
RN  - 0 (Toll-Like Receptor 1)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (Trans-Activators)
RN  - 0 (proto-oncogene protein Spi-1)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
SB  - IM
MH  - Cytokines/biosynthesis
MH  - Down-Regulation
MH  - Flow Cytometry
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/*physiology
MH  - Humans
MH  - Lipopolysaccharide Receptors/biosynthesis
MH  - Monocytes/*metabolism/physiology
MH  - Proto-Oncogene Proteins/*metabolism/physiology
MH  - RNA Interference
MH  - Real-Time Polymerase Chain Reaction
MH  - Toll-Like Receptor 1/biosynthesis
MH  - Toll-Like Receptor 2/biosynthesis
MH  - Toll-Like Receptor 4/biosynthesis
MH  - Toll-Like Receptors/*biosynthesis
MH  - Trans-Activators/*metabolism/physiology
PMC - PMC5047522
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/10/04 06:00
MHDA- 2017/06/15 06:00
PMCR- 2016/10/03
CRDT- 2016/10/04 06:00
PHST- 2015/12/10 00:00 [received]
PHST- 2016/08/28 00:00 [accepted]
PHST- 2016/10/04 06:00 [entrez]
PHST- 2016/10/04 06:00 [pubmed]
PHST- 2017/06/15 06:00 [medline]
PHST- 2016/10/03 00:00 [pmc-release]
AID - PONE-D-15-52061 [pii]
AID - 10.1371/journal.pone.0162667 [doi]
PST - epublish
SO  - PLoS One. 2016 Oct 3;11(10):e0162667. doi: 10.1371/journal.pone.0162667. 
      eCollection 2016.