title: Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis.
abstract: Th1 cytokine-induced loss of oligodendrocytes (OLs) is associated with axonal loss in CNS demyelinating diseases such as multiple sclerosis (MS)that contributes to neurological disabilities in affected individuals. Recent studies indicated that, in addition to Th1-phenotype cytokines including tumor necrosis factor (TNF)-α, Th17 phenotype cytokine, interleukin (IL)-17 also involved in the development of MS. In this study, we investigated the direct effect of IL-17 on the survival of OLs in the presence of TNF-α and individually in vitro settings. Our findings suggest that IL-17 alone, however, was not able to affect the survival of OLs, but it exacerbates the TNF-α-induced OL apoptosis as compared with individual TNF-α treatment. This effect of cytokines was ascribed to an inhibition of cell-survival mechanisms, co-localization of Bid/Bax proteins in the mitochondrial membrane and caspase 8 activation mediated release of apoptosis inducing factor from mitochondria in treated OLs. In addition, cytokine treatment disturbed the mitochondrial membrane potential in OLs with corresponding increase in the generation of reactive oxygen species, which were attenuated by N-acetyl cysteine treatment. In addition, combining of these cytokines induced cell-cycle arrest at G1/S phases in OL-like cells and inhibited the maturation of OL progenitor cells that was attenuated by peroxisome proliferator-activated receptor-γ/-β agonists. Collectively, these data provide initial evidence that IL-17 exacerbates TNF-α-induced OL loss and inhibits the differentiation of OL progenitor cells suggesting that antioxidant- or peroxisome proliferator-activated receptor agonist-based therapies have potential to limit CNS demyelination in MS or other related demyelinating disorders.
authors.affiliation: Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Paintlia
authors.forename: Ajaib S
authors.initials: AS
authors.lastname: Paintlia
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D006131:Growth Inhibitors; D020381:Interleukin-17; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha