Type I interferon signaling in systemic immune cells from patients with alcoholic cirrhosis and its association with outcome.
J Hepatol
; 66(5): 930-941, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-28040548
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-ß. 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. LAYSUMMARY:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucócitos Mononucleares
/
Transdução de Sinais
/
Interferon Tipo I
/
Cirrose Hepática Alcoólica
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
J Hepatol
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2017
Tipo de documento:
Article