Abstract
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 patients MS, 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 patients with MS and controls. Peripheral blood mononuclear cells 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 5years. pSTAT4 induction by IFN-β was lower in patients with MS than in controls, as was expression of IFNAR. pSTAT4 expression did not correlate with the clinical outcome at 5years, measured by EDSS change. There was a negative correlation between the baseline IFNAR1 mRNA levels and relapse rate. The results suggest decreased IFN-β 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-β treatment.
Highlights
The type I interferon, Interferon-β (IFN-β) has been used in the treatment of multiple sclerosis (MS) for many years [1, 2] and remains a mainstay disease modifying treatment for the relapsing forms of the disease
Production of type I IFN is deficient in patients with MS, and several studies showed a decreased responsiveness of MS patients to IFN type I [5, 6], reflected, for example, in reduced expression of IFN-stimulated genes and decreased phosphorylation of signal transducer and activator of transcription 1 (STAT1) [7]. The aim of this current study was to determine the effects of IFN-β on the phosphorylation of STAT4 in MS patients compared to controls as an indication of response to IFN-β, and to determine its relationship with the expression of interferon type 1 receptor (IFNAR)
We compared STAT4 activation in patients and controls. phosphorylated STAT4 (pSTAT4) induction was significantly higher in controls than in MS patients (MFI 98±5) (p = 0.031) (Figure 1)
Summary
The type I interferon, Interferon-β (IFN-β) has been used in the treatment of multiple sclerosis (MS) for many years [1, 2] and remains a mainstay disease modifying treatment for the relapsing forms of the disease. IFN-β, together with IFN-α utilises a shared heterodimeric receptor, IFNAR, composed of two chains, IFNAR1 and IFNAR2, and signals via Janus kinases Tyk and Jak, resulting in the formation of heterodimers of signal transducer and activator of transcription 1 (STAT1) and STAT2, which on translocation to the nucleus associate with IFN regulatory factor 9 (IRF9) forming the heterotrimeric complex IFN stimulated gene factor 3 (ISGF3). We aimed to determine if the effects of IFN-β on phosphorylation of STAT4 in MS patients correlate with their 5-year clinical course as measured by the change in the expanded disability scale (EDSS) score and clinical relapses
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