INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMR S_1149, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Laboratoire d'Excellence Inflamex, ComUE Sorbonne Paris Cité, Paris, France; Département d'Anesthésie et Réanimation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; INSERM, U970, Paris Cardiovascular Research Center - PARCC, Paris, France; UMR S_970, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
J Hepatol. 2017 May;66(5):930-941. doi: 10.1016/j.jhep.2016.12.008. Epub 2016 Dec 28.
BACKGROUND & AIMS: In immune cells, constitutively and acutely produced type I interferons (IFNs) engage autocrine/paracrine signaling pathways to induce IFN-stimulated genes (ISGs). Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. We aimed to investigate ISG expression in systemic immune cells from patients with decompensated alcoholic cirrhosis, and its association with outcome.
Peripheral blood mononuclear cells (PBMCs) from patients and heathy subjects were stimulated or not with lipopolysaccharide (LPS, an IFN inducer) or increasing concentrations of IFN-β. The expression of 48 ISGs and ten "non-ISG" inflammatory cytokines were analyzed using RT-qPCR.
We developed an 8-ISG signature (IFN score) assessing ISG expression. LPS-stimulated ISG induction was significantly lower in PBMCs from patients with cirrhosis compared to healthy controls. Non-ISGs, however, showed higher induction. Lower induction of ISGs by LPS was not due to decreased IFN production by cirrhotic PBMCs or neutralization of secreted IFN, but a defective PBMC response to IFN. This defect was at least in part due to decreased constitutive ISG expression. Patients with the higher baseline IFN scores and ISG levels had the higher risk of death. At baseline, "non-ISG" cytokines did not correlate with outcome.
PBMCs from patients with decompensated alcoholic cirrhosis exhibit downregulated ISG expression, both constitutively and after an acute stimulus. Our finding that higher baseline PBMC ISG expression was associated with higher risk of death, suggests that constitutive ISG expression in systemic immune cells contributes to the prognosis of alcoholic cirrhosis.
Enhanced activity of IFN signaling pathways can cause excessive inflammation and tissue damage. Here we show that peripheral blood mononuclear cells (PBMCs) from patients with alcoholic cirrhosis exhibit a defect in interferon-stimulated genes (ISGs). We found that higher baseline ISG expression in PBMCs was associated with higher risk of death, revealing a probable contribution of ISG expression in immune cells to the outcome of alcoholic cirrhosis.
在免疫细胞中，固有和急性产生的 I 型干扰素（IFN）通过自分泌/旁分泌信号通路诱导 IFN 刺激基因（ISG）。IFN 信号通路的过度激活可导致过度炎症和组织损伤。我们旨在研究失代偿期酒精性肝硬化患者外周血单个核细胞（PBMC）中的 ISG 表达及其与结局的关系。
用脂多糖（LPS，IFN 诱导剂）或递增浓度 IFN-β刺激或不刺激肝硬化患者和健康对照者的 PBMC，采用 RT-qPCR 分析 48 个 ISG 和 10 个“非 ISG”炎性细胞因子的表达。
我们建立了一个评估 ISG 表达的 8-ISG 特征（IFN 评分）。与健康对照者相比，肝硬化患者的 LPS 刺激的 ISG 诱导明显较低。然而，非 ISG 的诱导较高。LPS 诱导的 ISG 减少不是由于肝硬化 PBMC 产生 IFN 减少或分泌 IFN 中和，而是 PBMC 对 IFN 的反应缺陷。这种缺陷至少部分是由于组成性 ISG 表达减少所致。基线时 IFN 评分和 ISG 水平较高的患者死亡风险较高。在基线时，“非 ISG”细胞因子与结局无相关性。
失代偿期酒精性肝硬化患者的 PBMC 表现出组成性和急性刺激后下调的 ISG 表达。我们发现，基线时 PBMC 的更高 ISG 表达与更高的死亡风险相关，这表明系统性免疫细胞中的组成性 ISG 表达有助于酒精性肝硬化的预后。
IFN 信号通路的过度激活可导致过度炎症和组织损伤。在这里，我们表明酒精性肝硬化患者的外周血单个核细胞（PBMC）存在干扰素刺激基因（ISG）缺陷。我们发现，PBMC 中的基线 ISG 表达较高与死亡风险增加相关，这揭示了免疫细胞中 ISG 表达对酒精性肝硬化结局的可能贡献。
