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HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis

Authors :
Hisatake Matsumoto
Brendon P. Scicluna
Kin Ki Jim
Fahimeh Falahi
Wanhai Qin
Berke Gürkan
Erik Malmström
Mariska T. Meijer
Joe M. Butler
Hina N. Khan
Tsuyoshi Takagi
Shunsuke Ishii
Marcus J. Schultz
Diederik van de Beek
Alex F. de Vos
Cornelis van ‘t Veer
Tom van der Poll
Source :
Frontiers in Immunology, Vol 12 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

Our previous work identified human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) as a putative driver of LPS-induced NF-κB signaling in humans in vivo. While HIVEP1 is known to interact with NF-ĸB binding DNA motifs, its function in mammalian cells is unknown. We report increased HIVEP1 mRNA expression in monocytes from patients with sepsis and monocytes stimulated by Toll-like receptor agonists and bacteria. In complementary overexpression and gene deletion experiments HIVEP1 was shown to inhibit NF-ĸB activity and induction of NF-ĸB responsive genes. RNA sequencing demonstrated profound transcriptomic changes in HIVEP1 deficient monocytic cells and transcription factor binding site analysis showed enrichment for κB site regions. HIVEP1 bound to the promoter regions of NF-ĸB responsive genes. Inhibition of cytokine production by HIVEP1 was confirmed in LPS-stimulated murine Hivep1-/- macrophages and HIVEP1 knockdown zebrafish exposed to the common sepsis pathogen Streptococcus pneumoniae. These results identify HIVEP1 as a negative regulator of NF-κB in monocytes/macrophages that inhibits proinflammatory reactions in response to bacterial agonists in vitro and in vivo.

Details

Language :
English
ISSN :
16643224
Volume :
12
Database :
Directory of Open Access Journals
Journal :
Frontiers in Immunology
Publication Type :
Academic Journal
Accession number :
edsdoj.9fdd81d996c34400a7bfadd47712bee9
Document Type :
article
Full Text :
https://doi.org/10.3389/fimmu.2021.744358