The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis

Autoři: Giusi Prencipe aff001;  Claudia Bracaglia aff001;  Ivan Caiello aff001;  Antonia Pascarella aff001;  Paola Francalanci aff002;  Manuela Pardeo aff001;  Alessandra Meneghel aff003;  Giorgia Martini aff003;  Marianna N. Rossi aff001;  Antonella Insalaco aff001;  Giulia Marucci aff001;  Valerio Nobili aff004;  Marco Spada aff005;  Francesco Zulian aff003;  Fabrizio De Benedetti aff001
Působiště autorů: Division of Rheumatology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy aff001;  Department of Pathology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy aff002;  Department of Woman and Child Health, University of Padua, Padua, Italy aff003;  Hepatology Gastroenterology and Nutrition Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy aff004;  Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Aim of this study was to investigate the activation of the IFNγ 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 IFNγ-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 IFNγ-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 IFNγ 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 IFNγ-inducible genes were markedly increased. Accordingly, high circulating levels of IFNγ-inducible CXCL9 were observed in patients. Altogether, these data demonstrate the selective and marked up-regulation of the IFNγ pathway in the liver tissue and blood of patients with active sHLH. Finally, we show that measurement of circulating CXCL9 levels and evaluation of IFNγ–inducible gene expression levels in PBMCs may represent a new valid tool to better identify patients with suspected HLH with predominant liver involvement.

Klíčová slova:

Biopsy – Blood – Cytokines – Gene expression – Inflammatory diseases – Interferons – Liver diseases – T cells


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2019 Číslo 12
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