Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Front Immunol. 2021 Nov 5;12:744358. doi: 10.3389/fimmu.2021.744358. eCollection 2021.
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 . 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 macrophages and HIVEP1 knockdown zebrafish exposed to the common sepsis pathogen . These results identify HIVEP1 as a negative regulator of NF-κB in monocytes/macrophages that inhibits proinflammatory reactions in response to bacterial agonists and .
我们之前的工作确定了人类免疫缺陷病毒 I 型增强子结合蛋白 1（HIVEP1）是人类脂多糖诱导 NF-κB 信号的潜在驱动因素。虽然 HIVEP1 已知与 NF-ĸB 结合 DNA 基序相互作用，但它在哺乳动物细胞中的功能尚不清楚。我们报告了败血症患者单核细胞和 Toll 样受体激动剂和细菌刺激的单核细胞中 HIVEP1 mRNA 表达增加。在补充过表达和基因缺失实验中，HIVEP1 被证明抑制 NF-ĸB 活性和 NF-ĸB 反应基因的诱导。RNA 测序显示 HIVEP1 缺陷单核细胞中存在深刻的转录组变化，转录因子结合位点分析显示 κB 位点区域富集。HIVEP1 结合到 NF-ĸB 反应基因的启动子区域。在脂多糖刺激的小鼠巨噬细胞和暴露于常见败血症病原体的 HIVEP1 敲低斑马鱼中，证实了 HIVEP1 抑制细胞因子产生。这些结果确定 HIVEP1 是单核细胞/巨噬细胞中 NF-κB 的负调节剂，可抑制细菌激动剂引起的促炎反应。
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