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

Abstract

Objectives: Interferon-beta (IFN-beta) is used in the treatment of multiple sclerosis (MS). IFN-beta 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 patients MS, but data on interferon-alpha/beta receptor (IFNAR) expression and the relationship with treatment response are conflicting. Here, we compare IFN-beta-mediated STAT4 activation in immune cells of untreated patients with MS and controls. Material(s) and Method(s): Peripheral blood mononuclear cells from 27 untreated patients with relapsing MS, obtained before the initiation of IFN-beta treatment, and 12 matched controls were treated in vitro with IFN-beta. Total and phosphorylated STAT4 (pSTAT4) and IFNAR were measured by flow cytometry and quantitative PCR. The patients were followed up for 5 years. Result(s): pSTAT4 induction by IFN-beta was lower in patients with MS than in controls, as was expression of IFNAR. pSTAT4 expression did not correlate with the clinical outcome at 5 years, measured by EDSS change. There was a negative correlation between the baseline IFNAR1 mRNA levels and relapse rate. Conclusion(s): The results suggest decreased IFN-beta responsiveness in patients with MS, associated with reduced STAT4 activation and reduced IFNAR expression. This reduced responsiveness does not appear to affect the long-term clinical outcome of IFN-beta treatment.Copyright © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd