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Mult Scler. 2015 Sep;21(10):1262-70. doi: 10.1177/1352458514561909. Epub 2014 Dec 5.

Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis.

Author information

1
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany aiden.haghikia@rub.de andrew.chan@rub.de.
2
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Germany.
3
Department of Neurology at the University of California, San Francisco, USA.
4
Department of Human Genetics, Ruhr-University Bochum, Germany.
5
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.

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.

CONCLUSION:

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.

KEYWORDS:

Multiple sclerosis; PGC-1α; disease-modifying therapy (DMT); immune cellular energy metabolism; interferon-β; oxidative phosphorylation

PMID:
25480861
DOI:
10.1177/1352458514561909
[Indexed for MEDLINE]

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