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

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.

SUBMITTER: Matsumoto H

PROVIDER: S-EPMC8602905 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Matsumoto Hisatake H Scicluna Brendon P BP Jim Kin Ki KK Falahi Fahimeh F Qin Wanhai W Gürkan Berke B Malmström Erik E Meijer Mariska T MT Butler Joe M JM Khan Hina N HN Takagi Tsuyoshi T Ishii Shunsuke S Schultz Marcus J MJ van de Beek Diederik D de Vos Alex F AF van 't Veer Cornelis C van der Poll Tom T

Frontiers in immunology 20211105

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 <i>in vivo</i>. 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 experiment ...[more]

PMID: 34804025

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Project description:BackgroundTinospora cordifolia (Willd).Miers is a perennial climbing medicinal shrub that has been traditionally used for the treatment of chronic inflammatory ailments. Our previous pre- clinical studies on anti-inflammatory effects, proved that the chloroform extract of T. cordifolia (CETC) suppressed the LPS induced up-regulation of pro-inflammatory biomarkers, hence, further follow up study was carried out to evaluate whether CETC can exhibit a protective effect against LPS induced lethal endotoxemia in vivo and also to analyze the impact of CETC pre-treatment on the secretion of pro-inflammatory cytokines in vitro by THP-1 cells.MethodsTo corroborate our previous preclinical studies on inflammation, we investigated the mechanism of the anti-inflammatory effect of T. cordifolia on THP-cells which were pre-incubated with CETC (30 min) and stimulated subsequently with LPS (1 μg/ml) for 20 h. Levels as well as gene expressions of various cytokines were compared with that of LPS alone incubated cells. Alongside, in vivo oral anti-inflammatory efficacy against LPS induced endotoxemia study was effectuated, wherein rats were administered with CETC 48, 24, 12 and 1 h prior to the injection of LPS and the survival of rats were monitored upto 10 days. Cytokine levels were quantified by ELISA. Nitrite levels were measured using Griess reagent. Expression of pro-inflammatory proteins was inspected in rat tissues by histochemical and immuno -histochemical examinations.ResultsCETC was able to down-regulate the up-regulation of pro-inflammatory biomarkers in THP-1 macrophages though blockade of NF-κB nuclear translocation and could improve the survival rate during endotoxemic episodes with a marked suppression of the tissue expression of pro-inflammatory proteins.ConclusionThese findings concomitantly reveal the anti-inflammatory mechanism of CETC and support us to move forward for the development of drugs against disorders resulting from deregulated immune reactions.

Dataset Information

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

Publications

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

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