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J Hepatol. 2017 May;66(5):930-941. doi: 10.1016/j.jhep.2016.12.008. Epub 2016 Dec 28.

Type I interferon signaling in systemic immune cells from patients with alcoholic cirrhosis and its association with outcome.

Author information

1
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.
2
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.
3
INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMR S_1149, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
4
Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
5
INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMR S_1149, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology, HepatoPancreatology and Digestive Oncology, C.U.B. Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
6
Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India.
7
INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMR S_1149, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Service d'Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.
8
Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
9
INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMR S_1149, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
10
Genosplice Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
11
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; Service d'Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.
12
INSERM, U1149, Centre de Recherche sur l'Inflammation (CRI), Clichy and Paris, France; UMR S_1149, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Département d'Anesthésie et Réanimation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.
13
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.
14
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 Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France. Electronic address: richard.moreau@inserm.fr.

Abstract

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

LAY SUMMARY:

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.

KEYWORDS:

Cytokines; Inflammation; Innate immune response; Interferons; Leukocytes, mononuclear; Lipopolysaccharide; Liver cirrhosis; Liver cirrhosis, alcoholic; Prognosis

PMID:
28040548
DOI:
10.1016/j.jhep.2016.12.008
[Indexed for MEDLINE]

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