Decreased interferon-β induced STAT-4 activation in immune cells and clinical outcome in multiple sclerosis

Tanasescu, Radu; Midgley, Angela; Robins, R. Adrian; Constantinescu, Cris S.

Abstract

Objectives. Interferon-β (IFN-β) is used in the treatment of multiple sclerosis (MS). IFN-β activation of signal transduction and activation of transcription (STAT)-4 is linked to its immunomodulatory effects. Previous studies suggest a type I IFN deficit in immune cells of MS patients, but data on interferon-α/β receptor (IFNAR) expression and the relationship with treatment response are conflicting. Here we compare IFN-β-mediated STAT4 activation in immune cells of untreated MS patients and controls.
Materials & methods. Peripheral blood mononuclear cells (PBMC) from 27 untreated patients with relapsing MS, obtained before the initiation of IFN-β treatment, and 12 matched controls were treated in vitro with IFN-β. Total and phosphorylated STAT4 (pSTAT4) and IFNAR were measured by flow cytometry and quantitative PCR. The patients were followed-up for 5 years.
Results. pSTAT4 induction by IFN-β was lower in MS patients than in controls, as was expression of IFNAR. pSTAT4 expression did not correlate with the clinical outcome at five years, measured by EDSS change. There was a negative correlation between the baseline IFNAR1 mRNA levels and relapse rate.
Conclusions. The results suggest decreased IFN-β responsiveness in MS patients, associated with reduced STAT4 activation and reduced IFNAR expression. This reduced responsiveness does not appear to affect the long term clinical outcome of IFN-β treatment.

Citation

Tanasescu, R., Midgley, A., Robins, R. A., & Constantinescu, C. S. (in press). Decreased interferon-β induced STAT-4 activation in immune cells and clinical outcome in multiple sclerosis. Acta Neurologica Scandinavica, https://doi.org/10.1111/ane.12715

• Journal Article Type: Article
• Acceptance Date: Nov 11, 2016
• Online Publication Date: Dec 5, 2016
• Deposit Date: Feb 2, 2017
• Publicly Available Date: Feb 2, 2017
• Journal: Acta Neurologica Scandinavica
• Print ISSN: 0001-6314
• Electronic ISSN: 1600-0404
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1111/ane.12715
• Public URL: https://nottingham-repository.worktribe.com/output/836533
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1111/ane.12715/full
• Contract Date: Feb 2, 2017