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

• Published in: European journal of immunology 2017-11, Vol.47 (11), p.1918-1924
• Main Authors: Pirault, John, Polyzos, Konstantinos A., Petri, Marcelo H., Ketelhuth, Daniel F. J., Bäck, Magnus, Hansson, Göran K.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - biosynthesis; Adaptor Proteins, Vesicular Transport - immunology; Animals; Arteriosclerosis; Cardiovascular diseases; Gene Expression Regulation - immunology; Genome-wide association studies; Genomes; Hepatocyte; Hepatocytes; Hepatocytes - immunology; Hepatocytes - metabolism; Inflammation; Interferon; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interferon‐gamma; Janus Kinases - immunology; Janus Kinases - metabolism; Kexin; Lipid metabolism; Liver; Lymphocytes T; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Proprotein convertases; Signal transduction; Signal Transduction - immunology; Sortilin‐1; STAT Transcription Factors - immunology; STAT Transcription Factors - metabolism; STAT1; Subtilisin
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201646768

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. We demonstrated by cultures, chromatin immunoprecipitation assays and disruption of the JAK/STAT1 signaling pathway that the treatment of hepatocytes with the inflammatory cytokine IFN‐γ induced the repression of sortilin‐1.