Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis

Abstract

J. Neurochem. (2011) 116, 508–521. 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.

Direct and Indirect Effects of Immune and Central Nervous System–Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation

“…Indeed, TNF-a was demonstrated to cause degeneration of oligodendrocytes in the MS brain (4,24). Previous reports suggested that TNF-a inhibits survival and differentiation of OPCs in a model of spinal cord injury (SCI) (25), enhances oxidative stress-induced oligodendrocyte apoptosis (26), and mediates oligodendrocyte cell death through a TNFR1-dependent mechanism (27). Although our data support the previous work implicating TNF-a as a key cytokine that can dramatically influence oligodendrocyte biology (Fig.…”

Development of Cerebral Gray and White Matter Injury and Cerebral Inflammation over Time after Inflammatory Perinatal Asphyxia

“…The formation of free radicals, excitotoxicity, astrogliosis and release of cytokines by activated microglia are important downstream mechanisms that can damage the developing oligodendrocyte after inflammation and/or HI [53,65,66]. In particular, TNF-α has been described to negatively influencing oligodendrocyte maturation and/or induce oligodendrocyte death [53,67,68,69]. Apparently, the changes induced by LPS alone are not sufficient to induce white or gray matter damage in our mouse model.…”

Tumor Microenvironment Macrophage Inhibitory Factor Directs the Accumulation of Interleukin-17-producing Tumor-infiltrating Lymphocytes and Predicts Favorable Survival in Nasopharyngeal Carcinoma Patients

“…The increased percentage of Th17 cells in tumor tissues is associated with cytokines and chemokines released from tumor microenvironments (14,23,(41)(42)(43)(44). This study shows for the first time that the EBV ϩ C666 cells co-cultured with CD4 Six cytokines were found in the culture medium of NPC tumor tissues, with MIF being found in the greatest amount.…”