title: Decreased interferon-β induced STAT-4 activation in immune cells and clinical outcome in multiple sclerosis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 5 years.
  
  
  RESULTS
  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 5 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 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.
authors.affiliation: Division of Clinical Neuroscience, Clinical Neurology Research Group, Queen's Medical Centre, University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, UK.|Department of Clinical Neurosciences, University of Medicine and Pharmacy Carol Davila, Department of Neurology, Colentina Hospital, Bucharest, Romania.
authors.forename: R
authors.initials: R
authors.lastname: Tanasescu
authors.affiliation: Division of Clinical Neuroscience, Clinical Neurology Research Group, Queen's Medical Centre, University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Midgley
authors.affiliation: Division of Immunology, Clinical Neurology Research Group, Queen's Medical Centre, University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Robins
authors.affiliation: Division of Clinical Neuroscience, Clinical Neurology Research Group, Queen's Medical Centre, University of Nottingham, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Constantinescu
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: C508033:IFNAR2 protein, human; D050797:STAT4 Transcription Factor; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta
keywords: immunomodulation; interferon beta; multiple sclerosis