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Eur J Immunol. 2017 Nov;47(11):1918-1924. doi: 10.1002/eji.201646768. Epub 2017 Aug 14.

The inflammatory cytokine interferon-gamma inhibits sortilin-1 expression in hepatocytes via the JAK/STAT pathway.

Author information

1
Center for Molecular Medicine, Department of Medicine, Karolinska Institute, and Karolinska University Hospital, Stockholm, Sweden.
2
INSERM UMR_S1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France.

Abstract

Sortilin-1, a receptor of the VPS10p family, has been associated with cardiovascular disease in genome-wide association studies. It is implicated in lipoprotein metabolism, secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) and secretion of inflammatory cytokines. However, its own regulation remains unclear. Chronic inflammation is a hallmark of atherosclerosis and the absence of regulatory T (Treg) cells is associated with reduced protein expression of sortilin-1 in the liver. Therefore, we postulated that mediator(s) of inflammation known to be downregulated by Treg cells may modulate sortilin-1 expression. In this study, we identify interferon-gamma (IFN-γ) as the key inflammatory mediator controlling sortilin-1 levels. In vitro cultures of murine hepatocytes cell line and in silico experiments showed that the transcription factor Signal transducer and activator of transcription 1 was activated and bound to the Sort-1 gene upon IFN-γ treatment. This reduced the expression of sortilin-1, while disrupting the IFN-γ signaling pathway prevented the effect. These data unravel an intricate mechanism by which inflammation modulates receptors involved in lipoprotein turnover.

KEYWORDS:

Hepatocyte; Inflammation; Interferon-gamma; STAT1; Sortilin-1

PMID:
28742217
DOI:
10.1002/eji.201646768
[Indexed for MEDLINE]
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