Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice.
Animals
Anti-Inflammatory Agents
/ pharmacology
CCAAT-Enhancer-Binding Proteins
/ antagonists & inhibitors
Gene Expression Regulation
/ drug effects
Humans
Inflammation
/ chemically induced
Interleukin-10
/ genetics
Interleukin-1beta
/ genetics
Lipopolysaccharides
/ toxicity
Mice
Monocytes
/ drug effects
RNA
/ genetics
RNA, Messenger
/ genetics
Tumor Necrosis Factor-alpha
/ genetics
MTL-CEBPA
anti-inflammation
humanized mice
monocytes
saRNA
small activating RNA
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
08 05 2019
08 05 2019
Historique:
received:
29
11
2018
revised:
19
02
2019
accepted:
20
02
2019
pubmed:
11
3
2019
medline:
24
3
2020
entrez:
11
3
2019
Statut:
ppublish
Résumé
Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance.
Identifiants
pubmed: 30852139
pii: S1525-0016(19)30059-0
doi: 10.1016/j.ymthe.2019.02.018
pmc: PMC6520465
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
CCAAT-Enhancer-Binding Proteins
0
CEBPA protein, human
0
IL10 protein, human
0
IL1B protein, human
0
Interleukin-1beta
0
Lipopolysaccharides
0
RNA, Messenger
0
Tumor Necrosis Factor-alpha
0
Interleukin-10
130068-27-8
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
999-1016Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI029329
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI042552
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL074704
Pays : United States
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Nat Rev Immunol. 2003 Feb;3(2):169-76
pubmed: 12563300
J Clin Cell Immunol. 2013 Dec;4(6):
pubmed: 25133066
Blood. 1996 Feb 1;87(3):956-67
pubmed: 8562967
Immunol Rev. 2007 Jun;217:141-54
pubmed: 17498057
J Exp Med. 2005 Jul 4;202(1):85-96
pubmed: 15983063
Food Funct. 2010 Dec;1(3):254-61
pubmed: 21776474
Hepatology. 2014 Jan;59(1):216-27
pubmed: 23929703
Nat Biotechnol. 2010 Aug;28(8):839-47
pubmed: 20601939
Lancet. 2015 Jul 18;386(9990):258-65
pubmed: 25975452
Science. 1995 Aug 25;269(5227):1108-12
pubmed: 7652557
Nature. 1983 Feb 10;301(5900):527-30
pubmed: 6823332
Gastroenterology. 2011 May;140(6):1756-1767
pubmed: 21530742
J Theor Biol. 2004 Sep 21;230(2):145-55
pubmed: 15321710
J Immunol. 2016 Oct 15;197(8):3393-3405
pubmed: 27619993
Curr Pharm Biotechnol. 2018;19(8):611-621
pubmed: 29886828
Ann Transl Med. 2016 Nov;4(21):438
pubmed: 27942529
Gene. 1994 Nov 18;149(2):305-10
pubmed: 7959007
Annu Rev Med. 1987;38:417-32
pubmed: 3555304
Nature. 1994 Nov 3;372(6501):103-7
pubmed: 7969402
Mol Ther. 2017 Dec 6;25(12):2705-2714
pubmed: 28882451
Front Immunol. 2017 Dec 12;8:1728
pubmed: 29312290
J Neuroinflammation. 2016 Mar 24;13(1):67
pubmed: 27012931
J Exp Med. 1998 Sep 21;188(6):1173-84
pubmed: 9743535
PLoS One. 2014 Apr 21;9(4):e95784
pubmed: 24752325
J Immunol. 2001 May 1;166(9):5646-53
pubmed: 11313405
J Transl Med. 2012 Sep 13;10:190
pubmed: 22974474
DNA Cell Biol. 1995 Sep;14(9):795-802
pubmed: 7669256
Trends Biochem Sci. 2016 Dec;41(12):1012-1021
pubmed: 27669650
J Cancer Res Clin Oncol. 2009 Feb;135(2):241-7
pubmed: 18663475
Genes Chromosomes Cancer. 2012 Apr;51(4):313-27
pubmed: 22170698
Prostate. 2009 Jun 15;69(9):1001-16
pubmed: 19347879
Annu Rev Virol. 2017 Sep 29;4(1):393-412
pubmed: 28746819
Anticancer Res. 2003 Jan-Feb;23(1A):351-4
pubmed: 12680236
Mol Cell Biol. 1998 Jul;18(7):4301-14
pubmed: 9632814
Blood Cells Mol Dis. 2003 Nov-Dec;31(3):338-41
pubmed: 14636649
Adv Exp Med Biol. 2017;983:189-194
pubmed: 28639200
Crit Care Med. 2009 Jan;37(1):291-304
pubmed: 19050640
Biomed Res Int. 2014;2014:264859
pubmed: 24839602
J Biol Chem. 1992 Mar 15;267(8):5021-4
pubmed: 1371993
Oncogene. 2017 Sep 14;36(37):5221-5230
pubmed: 28504718
J Mol Endocrinol. 2013 Nov 07;51(3):287-99
pubmed: 23969982
Biomed Pharmacother. 2017 Aug;92:175-186
pubmed: 28549290
J Biol Chem. 1998 Nov 6;273(45):29279-82
pubmed: 9792624
Sci Rep. 2017 Oct 25;7(1):14048
pubmed: 29070836
Nature. 2008 Jul 24;454(7203):436-44
pubmed: 18650914
Int Immunopharmacol. 2013 Feb;15(2):442-9
pubmed: 23352443
Oncogene. 2018 Jun;37(24):3216-3228
pubmed: 29511346
Annu Rev Biochem. 2002;71:635-700
pubmed: 12045108
J Immunol. 2014 Dec 15;193(12):6152-60
pubmed: 25398328
J Immunol. 2007 May 15;178(10):6342-9
pubmed: 17475863
Cancer Res. 2002 Jan 15;62(2):528-34
pubmed: 11809705
Antonie Van Leeuwenhoek. 2018 Jul;111(7):1023-1031
pubmed: 29255999
J Neuroinflammation. 2015 Apr 17;12:74
pubmed: 25890375
Ann Rheum Dis. 2014 Jun;73(6):1202-10
pubmed: 23687262
Clin Cancer Res. 2005 May 1;11(9):3184-90
pubmed: 15867211
J Invest Dermatol. 2007 Mar;127(3):514-25
pubmed: 17299434
Nature. 2002 Dec 19-26;420(6917):860-7
pubmed: 12490959
Curr Opin Genet Dev. 1995 Oct;5(5):565-70
pubmed: 8664543
Sci Rep. 2015 Sep 28;5:14488
pubmed: 26412089
J Virol. 2018 Mar 14;92(7):
pubmed: 29343582
Postgrad Med. 2010 Sep;122(5):125-33
pubmed: 20861596
J Neurosci Res. 2007 Apr;85(5):985-93
pubmed: 17253645
Cancer Res. 2016 Dec 1;76(23):6778-6784
pubmed: 27530323
Cancer Res. 2007 May 15;67(10):4657-64
pubmed: 17510391
AACN Clin Issues. 2004 Jan-Mar;15(1):3-17
pubmed: 14767362
Microbiol Spectr. 2016 Dec;4(6):
pubmed: 28084208
Mol Cell Biol. 1993 Nov;13(11):7191-8
pubmed: 8413306
Infect Immun. 2013 May;81(5):1520-31
pubmed: 23439310