Interferon‐γ inhibits cell cycle exit in differentiating oligodendrocyte progenitor cells

Abstract

The developmental processes of the oligodendrocyte progenitor cell (OPC) lineage that are targeted by interferon-gamma (IFN-gamma) were studied in primary rat OPC cultures. Under conditions of thyroid hormone-mediated oligodendrocyte differentiation, IFN-gamma produced a dose-dependent apoptotic response in OPCs. The lowest dose tested (15 ng/ml or 75 U/ml) was nonapoptotic, but activated detectable STAT1 DNA-binding. At this dose, IFN-gamma reduced the percentage of mature O1+ cells and increased the percentage of immature A2B5+ OPCs. This was observed without significant change in total cell number and cytotoxicity, and was accompanied by an increase in BrdU-labeled A2B5+ and O4+ cells. FACS analysis confirmed a lack of apoptotic sub-G1 cells and revealed a greater percentage of S- and G2/M-phase OPCs with IFN-gamma treatment. Dual immunostaining with Ki-67 and Olig2 showed a smaller percentage of Olig2+ cells in G0 phase in IFN-gamma-treated OPCs, indicating loss of G1 control. Instead, increased levels and phosphorylation of the checkpoint protein p34cdc2 by IFN- suggested increased partial arrest in G2. IFN-gamma not only sustained expression of PCNA and the G1-S regulators retinoblastoma protein, cyclin D1, cyclin E, and cdk2, but also decreased p27 levels. In addition to changes in cell proliferation and differentiation, IFN-gamma attenuated myelin basic protein (MBP) expression significantly, which was associated with decreased expression of both MBP and Sox10 RNAs. These findings indicate that IFN-gamma not only maintains cell cycle activity that could predispose OPCs to apoptosis, but also overrides G1-G0 signals leading to thyroid hormone-mediated terminal differentiation and myelin gene expression.

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

“…[3][4][5]59,60 The latter (IFN-g)was shown to inhibit cell cycle exit in oligodendrocyte progenitor cells and attenuate MBP expression. 61 Taken together, these previous data point to an alternative view that activated astrocytes and microglia in brains of CPZ-treated mice may contribute to or exacerbate mature oligodendrocyte loss and myelin breakdown as shown in this study. It implies that antiinflammatory treatment or inhibiting astrocyte and microglia activation may be of help in improving the CPZinduced white matter damage.…”

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

“…However, IFN-␥ mRNA was not detectable in all mice, and the fold increase was small. Other studies have demonstrated that IFN-␥ can both inhibit differentiation and induce apoptosis of OPCs, 60,61 as well as protect mature oligodendrocytes against cuprizone-induced destruction 62 and inflammatory destruction, 63 which suggests that the effect of IFN-␥ on the oligodendrocyte population is context-dependent. However, although our finding of a several hundred-fold increase in IFN-␥ mRNA expression in the PP-lesioned T PLP mice raises the possibility of a role for IFN-␥ in the oligodendrotrophic effect of the myelin-reactive T cells, it is noteworthy that IFN-␥ mRNA detectable via in situ hybridization was expressed by rare cells, presumed to be T cells, located outside of the molecular layer of the dentate gyrus.…”

Suppressor of Cytokine Signaling 1 Expression Protects Oligodendrocytes from the Deleterious Effects of Interferon-γ

“…Studies using purified oligodendrocytes in vitro, however, suggest that the cytokine may have a direct, harmful effect on oligodendrocytes (Torres et al, 1995;Agresti et al, 1996;Andrews et al, 1998;Baerwald and Popko, 1998;Lin et al, 2005). IFN-␥ has been shown to inhibit cell cycle exit of oligodendroglial progenitor cells, which may predispose these cells to apoptotic death (Chew et al, 2005). Additionally, IFN-␥ has been shown to be a very powerful apoptosis-inducing agent for developing oligodendrocytes (Baerwald and Popko, 1998;Baerwald et al, 2000;Lin et al, 2005).…”