Division of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel.
PLoS One. 2013 Apr 23;8(4):e62366. doi: 10.1371/journal.pone.0062366. Print 2013.
Monocytes, which are key players in innate immunity, are outnumbered by neutrophils and lymphocytes among peripheral white blood cells. The cytokine interferon-β (IFN-β) is widely used as an immunomodulatory drug for multiple sclerosis and its functional pathways in peripheral blood mononuclear cells (PBMCs) have been previously described. The aim of the present study was to identify novel, cell-specific IFN-β functions and pathways in tumor necrosis factor (TNF)-α-activated monocytes that may have been missed in studies using PBMCs.
METHODOLOGY/PRINCIPAL FINDINGS: Whole genome gene expression profiles of human monocytes and T cells were compared following in vitro priming to TNF-α and overnight exposure to IFN-β. Statistical analyses of the gene expression data revealed a cell-type-specific change of 699 transcripts, 667 monocyte-specific transcripts, 21 T cell-specific transcripts and 11 transcripts with either a difference in the response direction or a difference in the magnitude of response. RT-PCR revealed a set of differentially expressed genes (DEGs), exhibiting responses to IFN-β that are modulated by TNF-α in monocytes, such as RIPK2 and CD83, but not in T cells or PBMCs. Known IFN-β promoter response elements, such as ISRE, were enriched in T cell DEGs but not in monocyte DEGs. The overall directionality of the gene expression regulation by IFN-β was different in T cells and monocytes, with up-regulation more prevalent in T cells, and a similar extent of up and down-regulation recorded in monocytes.
By focusing on the response of distinct cell types and by evaluating the combined effects of two cytokines with pro and anti-inflammatory activities, we were able to present two new findings First, new IFN-β response pathways and genes, some of which were monocytes specific; second, a cell-specific modulation of the IFN-β response transcriptome by TNF-α.
单核细胞是先天免疫的关键细胞，在外周白细胞中数量少于中性粒细胞和淋巴细胞。细胞因子干扰素-β（IFN-β）被广泛用作多发性硬化症的免疫调节剂，其在外周血单个核细胞（PBMC）中的功能途径已被先前描述。本研究旨在鉴定 TNF-α 激活的单核细胞中新型、细胞特异性 IFN-β 功能和途径，这些功能和途径可能在使用 PBMC 的研究中被忽略。
方法/主要发现：在体外用 TNF-α 诱导人单核细胞和 T 细胞后，比较它们的全基因组基因表达谱，并在 overnight 暴露于 IFN-β 后，对基因表达数据进行统计分析。结果显示，699 个转录本、667 个单核细胞特异性转录本、21 个 T 细胞特异性转录本和 11 个转录本具有细胞类型特异性变化，其反应方向或反应幅度不同。RT-PCR 揭示了一组差异表达基因（DEGs），这些基因在单核细胞中对 IFN-β 的反应受 TNF-α调节，如 RIPK2 和 CD83，但在 T 细胞或 PBMC 中不受调节。已知的 IFN-β 启动子反应元件，如 ISRE，在 T 细胞 DEGs 中富集，但在单核细胞 DEGs 中没有富集。IFN-β 对 T 细胞和单核细胞的基因表达调控的总体方向性不同，T 细胞中上调更为常见，而单核细胞中上调和下调的程度相似。
通过关注不同细胞类型的反应，并评估两种具有促炎和抗炎活性的细胞因子的联合作用，我们能够提出两个新发现：首先，新的 IFN-β 反应途径和基因，其中一些是单核细胞特异性的；其次，TNF-α 对 IFN-β 反应转录组具有细胞特异性的调节作用。
