title: Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis.
abstract: BACKGROUND
  Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism.
  
  
  OBJECTIVE
  The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4(+) T cells.
  
  
  METHODS
  Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4(+) cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (ΔΨm) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4(+) cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed.
  
  
  RESULTS
  IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4(+) T cells compared to controls (p < 0.001). Mitochondrial effects were reflected by depolarization of ΔΨm. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders (p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels.
  
  
  CONCLUSIONS
  Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4(+) T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany aiden.haghikia@rub.de andrew.chan@rub.de.
authors.forename: Aiden
authors.initials: A
authors.lastname: Haghikia
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Faissner
authors.affiliation: Department of Neurology at the University of California, San Francisco, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Pappas
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pula
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Arning
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ruhrmann
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Duscha
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Neurology at the University of California, San Francisco, USA.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.
authors.forename: Sunny
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016899:Interferon-beta / Q000378:metabolism* / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy*
chemical_list: D016899:Interferon-beta
keywords: Multiple sclerosis; PGC-1α; disease-modifying therapy (DMT); immune cellular energy metabolism; interferon-β; oxidative phosphorylation