Interferon-beta affects mitochondrial activity in CD4+ lymphocytes: Implications for mechanism of action in multiple sclerosis. (September 2015)

• Record Type: Journal Article
• Authors: Haghikia, Aiden; Faissner, Simon; Pappas, Derek; Pula, Bartosz; Akkad, Denis A; Arning, Larissa; Ruhrmann, Sabrina; Duscha, Alexander; Gold, Ralf; Baranzini, Sergio E; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Chan, Andrew
• Is Part Of: Multiple sclerosis. Volume 21:Number 10(2015)
• Page Start: 1262
• Page End: 1270
• Publication Date: 2015-09
• Subjects: Multiple sclerosis -- disease-modifying therapy (DMT) -- interferon-β -- immune cellular energy metabolism -- PGC-1α -- oxidative phosphorylation; Central nervous system -- Diseases -- Periodicals; Myelin sheath -- Diseases -- Periodicals; Inflammation -- Periodicals; Multiple sclerosis -- Periodicals; Central Nervous System Diseases -- Periodicals; Demyelinating Diseases -- Periodicals; Inflammation -- Periodicals; Multiple Sclerosis -- Periodicals; Système nerveux central -- Maladies -- Périodiques; Gaine de myéline -- Maladies -- Périodiques; Inflammation (Pathologie) -- Périodiques; Sclérose en plaques -- Périodiques; Electronic journals; 616.834005
• DOI: 10.1177/1352458514561909
• Languages: English
• ISSNs: 1352-4585

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.