The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis
The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis
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DOI：
10.1371/journal.pone.0226043
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发表时间：
2019-12-17
期刊：
影响因子：
3.7
通讯作者：
De Benedetti, Fabrizio
中科院分区：
文献类型：
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作者：
Prencipe, Giusi;Bracaglia, Claudia;De Benedetti, Fabrizio
本研究的目的是探讨继发性噬血细胞性淋巴组织细胞增生症（sHLH）患者的肝脏和血液中IFN γ通路的激活情况。为了这个目的，IFNG和IFN γ诱导基因的mRNA表达水平以及酪氨酸（701）磷酸化的信号转导和转录激活因子1（STAT1）蛋白水平进行了评估，在肝脏和外周血单核细胞（PBMC）的3例sHLH与主要的肝脏参与。IFNG和IFN γ诱导基因的mRNA表达水平在患者肝脏中显著高于对照肝脏和一种疾病对照肝脏。相反，I型IFN诱导基因和其他经典炎症细胞因子基因的表达水平略有差异，进一步支持IFN γ途径的激活，与对照组相比，在患者肝脏中检测到更高的磷酸化和总STAT1蛋白水平。当在肝活检前从3名患者中的2名收集的PBMC中评估在肝组织中分析的相同基因的表达时，我们发现IFN γ诱导基因的mRNA水平显著增加。因此，在患者中观察到高循环水平的IFN γ诱导型CXCL9。总之，这些数据证明了在具有活性sHLH的患者的肝组织和血液中IFN γ途径的选择性和显著上调。最后，我们表明，循环CXCL9水平的测量和评估IFN γ诱导的基因表达水平的PBMC可能是一个新的有效的工具，以更好地确定可疑的HLH患者与主要的肝脏参与。
Aim of this study was to investigate the activation of the IFN gamma pathway in the affected liver and in the blood of patients with secondary hemophagocytic lymphohistiocytosis (sHLH). To this purpose, the mRNA expression levels of IFNG and IFN gamma-inducible genes as well as Tyrosine (701)-phosphorylated signal transducer and activator of transcription 1 (STAT1) protein levels were evaluated in the liver and in peripheral blood mononuclear cells (PBMCs) of three patients with sHLH with predominant liver involvement. The mRNA expression levels of IFNG and IFN gamma-inducible genes were markedly higher in patient livers compared to control livers and to one disease control liver. Conversely, slight differences in the expression levels of Type I IFN-inducible genes and other classical inflammatory cytokine genes were found. Further supporting the activation of the IFN gamma pathway, higher protein levels of phosphorylated and total STAT1 were detected in patient livers compared to control livers. When the expression of the same genes analysed in liver tissues was evaluated in PBMCs collected from 2 out of 3 patients before the liver biopsy, we found that mRNA levels of IFN gamma-inducible genes were markedly increased. Accordingly, high circulating levels of IFN gamma-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFN gamma pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFN gamma-inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.