PMID- 36139421
OWN - NLM
STAT- MEDLINE
DCOM- 20220926
LR  - 20221129
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 18
DP  - 2022 Sep 12
TI  - A BET Protein Inhibitor Targeting Mononuclear Myeloid Cells Affects Specific 
      Inflammatory Mediators and Pathways in Crohn's Disease.
LID - 10.3390/cells11182846 [doi]
LID - 2846
AB  - BACKGROUND: Myeloid cells are critical determinants of the sustained inflammation 
      in Crohn's Disease (CD). Targeting such cells may be an effective therapeutic 
      approach for refractory CD patients. Bromodomain and extra-terminal domain 
      protein inhibitors (iBET) are potent anti-inflammatory agents; however, they also 
      possess wide-ranging toxicities. In the current study, we make use of a BET 
      inhibitor containing an esterase sensitive motif (ESM-iBET), which is cleaved by 
      carboxylesterase-1 (CES1), a highly expressed esterase in mononuclear myeloid 
      cells. METHODS: We profiled CES1 protein expression in the intestinal biopsies, 
      peripheral blood, and CD fistula tract (fCD) cells of CD patients using mass 
      cytometry. The anti-inflammatory effect of ESM-iBET or its control (iBET) were 
      evaluated in healthy donor CD14(+) monocytes and fCD cells, using cytometric 
      beads assay or RNA-sequencing. RESULTS: CES1 was specifically expressed in 
      monocyte, macrophage, and dendritic cell populations in the intestinal tissue, 
      peripheral blood, and fCD cells of CD patients. ESM-iBET inhibited IL1beta, IL6, and 
      TNFalpha secretion from healthy donor CD14(+) monocytes and fCD immune cells, with 
      10- to 26-fold more potency over iBET in isolated CD14(+) monocytes. 
      Transcriptomic analysis revealed that ESM-iBET inhibited multiple inflammatory 
      pathways, including TNF, JAK-STAT, NF-kB, NOD2, and AKT signaling, with superior 
      potency over iBET. CONCLUSIONS: We demonstrate specific CES1 expression in 
      mononuclear myeloid cell subsets in peripheral blood and inflamed tissues of CD 
      patients. We report that low dose ESM-iBET accumulates in CES1-expressing cells 
      and exerts robust anti-inflammatory effects, which could be beneficial in 
      refractory CD patients.
FAU - Elfiky, Ahmed M I
AU  - Elfiky AMI
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Hageman, Ishtu L
AU  - Hageman IL
AUID- ORCID: 0000-0002-3180-156X
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
AD  - Department of Gastroenterology and Hepatology, Amsterdam University Medical 
      Centers, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), University 
      of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
FAU - Becker, Marte A J
AU  - Becker MAJ
AUID- ORCID: 0000-0002-7881-4958
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
FAU - Verhoeff, Jan
AU  - Verhoeff J
AUID- ORCID: 0000-0003-0648-0642
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
AD  - Department of Molecular Cell Biology & Immunology, Amsterdam Infection & Immunity 
      Institute and Cancer Center Amsterdam, Amsterdam University Medical Centers, Free 
      University Amsterdam, 1081 HV Amsterdam, The Netherlands.
FAU - Li Yim, Andrew Y F
AU  - Li Yim AYF
AUID- ORCID: 0000-0002-0754-0953
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
AD  - Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam 
      Reproduction & Development, Amsterdam University Medical Centers, University of 
      Amsterdam, 1105 AZ Amsterdam, The Netherlands.
FAU - Joustra, Vincent W
AU  - Joustra VW
AUID- ORCID: 0000-0003-4157-7220
AD  - Department of Gastroenterology and Hepatology, Amsterdam University Medical 
      Centers, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), University 
      of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
FAU - Mulders, Lieven
AU  - Mulders L
AD  - Department of Gastroenterology and Hepatology, Amsterdam University Medical 
      Centers, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), University 
      of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
FAU - Fung, Ivan
AU  - Fung I
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
FAU - Rioja, Inmaculada
AU  - Rioja I
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Prinjha, Rab K
AU  - Prinjha RK
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Smithers, Nicholas N
AU  - Smithers NN
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Furze, Rebecca C
AU  - Furze RC
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Mander, Palwinder K
AU  - Mander PK
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Bell, Matthew J
AU  - Bell MJ
AD  - Immunology Research Unit, GSK Medicines Research Centre, Stevenage SG1 2FX, UK.
FAU - Buskens, Christianne J
AU  - Buskens CJ
AUID- ORCID: 0000-0001-9425-8683
AD  - Department of Surgery, Amsterdam UMC, University of Amsterdam, 1081 HV Amsterdam, 
      The Netherlands.
FAU - D'Haens, Geert R
AU  - D'Haens GR
AD  - Department of Gastroenterology and Hepatology, Amsterdam University Medical 
      Centers, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), University 
      of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
FAU - Wildenberg, Manon E
AU  - Wildenberg ME
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
FAU - de Jonge, Wouter J
AU  - de Jonge WJ
AUID- ORCID: 0000-0002-3241-1547
AD  - Tytgat Institute for Liver and Intestinal and Research, Amsterdam 
      Gastroenterology & Metabolism, Amsterdam University Medical Centers, University 
      of Amsterdam, 1105 BK Amsterdam, The Netherlands.
AD  - Department of Surgery, University of Bonn, 53127 Bonn, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220912
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Interleukin-6)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.1.- (Carboxylic Ester Hydrolases)
SB  - IM
MH  - *Anti-Inflammatory Agents/pharmacology/therapeutic use
MH  - Carboxylic Ester Hydrolases
MH  - *Crohn Disease/drug therapy/metabolism
MH  - Humans
MH  - Inflammation Mediators
MH  - Interleukin-6
MH  - Myeloid Cells/metabolism
MH  - NF-kappa B
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA
MH  - Tumor Necrosis Factor-alpha
PMC - PMC9497176
OTO - NOTNLM
OT  - BET inhibitor
OT  - CES1
OT  - IBD
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest. NS, IR, RP, RF, HL, PM, and MB were employed by GSK at the 
      time this study was conducted. AE, MG, IH, JV, AY, MJB, MW, GD, CB, IF, LM, VJ, 
      and WJ were employed by Amsterdam University Medical Centers at the time this 
      study was conducted.
EDAT- 2022/09/24 06:00
MHDA- 2022/09/28 06:00
PMCR- 2022/09/12
CRDT- 2022/09/23 01:06
PHST- 2022/06/15 00:00 [received]
PHST- 2022/08/08 00:00 [revised]
PHST- 2022/09/06 00:00 [accepted]
PHST- 2022/09/23 01:06 [entrez]
PHST- 2022/09/24 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2022/09/12 00:00 [pmc-release]
AID - cells11182846 [pii]
AID - cells-11-02846 [pii]
AID - 10.3390/cells11182846 [doi]
PST - epublish
SO  - Cells. 2022 Sep 12;11(18):2846. doi: 10.3390/cells11182846.