PMID- 30568658
OWN - NLM
STAT- MEDLINE
DCOM- 20191025
LR  - 20200309
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 9
DP  - 2018
TI  - Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate 
      Lyase.
PG  - 2858
LID - 10.3389/fimmu.2018.02858 [doi]
LID - 2858
AB  - Macrophages exposed to the Th2 cytokines interleukin (IL) IL-4 and IL-13 exhibit 
      a distinct transcriptional response, commonly referred to as M2 polarization. 
      Recently, IL-4-induced polarization of murine bone marrow-derived macrophages 
      (BMDMs) has been linked to acetyl-CoA levels through the activity of the 
      cytosolic acetyl-CoA-generating enzyme ATP-citrate lyase (ACLY). Here, we studied 
      how ACLY regulated IL-4-stimulated gene expression in human monocyte-derived 
      macrophages (MDMs). Although multiple ACLY inhibitors attenuated IL-4-induced 
      target gene expression, this effect could not be recapitulated by silencing ACLY 
      expression. Furthermore, ACLY inhibition failed to alter cellular acetyl-CoA 
      levels and histone acetylation. We generated ACLY knockout human THP-1 
      macrophages using CRISPR/Cas9 technology. While these cells exhibited reduced 
      histone acetylation levels, IL-4-induced gene expression remained intact. 
      Strikingly, ACLY inhibitors still suppressed induction of target genes by IL-4 in 
      ACLY knockout cells, suggesting off-target effects of these drugs. Our findings 
      suggest that ACLY may not be the major regulator of nucleocytoplasmic acetyl-CoA 
      and IL-4-induced polarization in human macrophages. Furthermore, caution should 
      be warranted in interpreting the impact of pharmacological inhibition of ACLY on 
      gene expression.
FAU - Namgaladze, Dmitry
AU  - Namgaladze D
AD  - Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Frankfurt, 
      Germany.
FAU - Zukunft, Sven
AU  - Zukunft S
AD  - Center for Molecular Medicine, Institute for Vascular Signaling, 
      Goethe-University, Frankfurt, Germany.
FAU - Schnutgen, Frank
AU  - Schnutgen F
AD  - Department of Medicine 2, LOEWE Center for Cell and Gene Therapy and Frankfurt 
      Cancer Institute, University Hospital Frankfurt, Goethe-University, Frankfurt, 
      Germany.
FAU - Kurrle, Nina
AU  - Kurrle N
AD  - Department of Medicine 2, LOEWE Center for Cell and Gene Therapy and Frankfurt 
      Cancer Institute, University Hospital Frankfurt, Goethe-University, Frankfurt, 
      Germany.
FAU - Fleming, Ingrid
AU  - Fleming I
AD  - Center for Molecular Medicine, Institute for Vascular Signaling, 
      Goethe-University, Frankfurt, Germany.
FAU - Fuhrmann, Dominik
AU  - Fuhrmann D
AD  - Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Frankfurt, 
      Germany.
FAU - Brune, Bernhard
AU  - Brune B
AD  - Faculty of Medicine, Institute of Biochemistry I, Goethe-University, Frankfurt, 
      Germany.
AD  - Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute 
      for Molecular Biology and Applied Ecology, IME, Frankfurt, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181204
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (Histones)
RN  - 0 (IL4 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 207137-56-2 (Interleukin-4)
RN  - 72-89-9 (Acetyl Coenzyme A)
RN  - EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase)
SB  - IM
MH  - ATP Citrate (pro-S)-Lyase/antagonists & 
      inhibitors/genetics/immunology/*metabolism
MH  - Acetyl Coenzyme A/metabolism
MH  - Acetylation/drug effects
MH  - Blood Buffy Coat/cytology
MH  - Gene Expression Regulation/drug effects/immunology
MH  - Gene Knockdown Techniques
MH  - Histones/metabolism
MH  - Humans
MH  - Interleukin-4/immunology/*metabolism
MH  - Macrophage Activation/*drug effects
MH  - Macrophages/enzymology/*immunology
MH  - Primary Cell Culture
MH  - RNA, Small Interfering/metabolism
MH  - THP-1 Cells
PMC - PMC6290342
OTO - NOTNLM
OT  - ATP-citrate lyase
OT  - acetyl-CoA
OT  - histone acetylation
OT  - interleukin-4
OT  - macrophage
EDAT- 2018/12/21 06:00
MHDA- 2019/10/28 06:00
PMCR- 2018/01/01
CRDT- 2018/12/21 06:00
PHST- 2018/09/20 00:00 [received]
PHST- 2018/11/20 00:00 [accepted]
PHST- 2018/12/21 06:00 [entrez]
PHST- 2018/12/21 06:00 [pubmed]
PHST- 2019/10/28 06:00 [medline]
PHST- 2018/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2018.02858 [doi]
PST - epublish
SO  - Front Immunol. 2018 Dec 4;9:2858. doi: 10.3389/fimmu.2018.02858. eCollection 
      2018.