MEK-ERK Signaling Is Involved in Interferon-γ-induced Death of Oligodendroglial Progenitor Cells*

Abstract

Oligodendrocytes are exposed to various cytokines in inflammatory lesions in the central nervous system. In this study, we focused on the direct effects of interferon-␥ (IFNG) on highly purified rat oligodendroglial cultures at different developmental stages. Among the three stages tested, IFNG had direct cytotoxic effects on actively proliferating oligodendrocyte progenitors but much less on immature oligodendrocytes and none on mature oligodendrocytes. This stage-specific susceptibility of progenitors to IFNG-induced cytotoxicity consisted of two components, delay in the G 1 /S transition of the cell cycle and increased cell death at least partly mediated by apoptosis, suggesting that progression of the cell cycle was tightly linked to this toxic mechanism. There was no functional difference in the signal transducers and activators of transcription (STAT) pathways between progenitors and mature oligodendrocytes as determined by induction of IRF1 mRNA in response to IFNG. We found that partial inhibition of the MEK-ERK pathway, one of the mitogen-activated protein kinase phosphorelay modules, by U0126 partially reversed the IFNG-induced cytotoxicity in progenitors. In addition, ERK activity was quickly down-regulated after in vitro differentiation of progenitors to immature oligodendrocytes. Therefore, we concluded that simultaneous activation of the STAT pathway by IFNG and of the ERK pathway by exogenous trophic factors played a role in the stage-specific IFNG-induced cytotoxicity in oligodendroglial progenitors. Our study has implications with respect to the mechanisms of periventricular leukomalacia in infants and of persistent demyelination in multiple sclerosis lesions in adults.

Inhibition of the EGF receptor and ERK1/2 signaling pathways rescues the human epidermoid carcinoma A431 cells from IFNγ-induced apoptosis

“…Furthermore, IFNγ-induced cytotoxicity is often accompanied by IFNγ-induced ERK activation. 4,27 While IFNγ is known to inhibit cell growth in the human epidermoid carcinoma A431 cell line, 5,6 the molecular mechanism underlying antiproliferative effect of IFNγ remains obscure. Furtermore, implication of both EGFR transactivation and ERK1/2 activation in the growth inhibitory action of IFNγ has not yet been described.…”

“…However, accumulating evidence has demonstrated a pro-apoptotic function of ERK1/2 under certain experimental conditions, [49][50][51][52] including IFNγ stimulation. 4,27 Importantly, MEK inhibition by U0126 rescued various types of the cells from IFNγ-initiated death. 4,27 The recent report by Mebratu et al announced a new molecular mechanism of IFNγ-induced cell death in human airway epithelial cells (HAECs), in which BH3-only protein Bik is the central mediator of apoptosis.…”

“…4,27 Importantly, MEK inhibition by U0126 rescued various types of the cells from IFNγ-initiated death. 4,27 The recent report by Mebratu et al announced a new molecular mechanism of IFNγ-induced cell death in human airway epithelial cells (HAECs), in which BH3-only protein Bik is the central mediator of apoptosis. Bik was shown to interact directly with and suppress nuclear translocation of phospho-ERK1/2.…”

“…23,24 STAT1 has been implicated in apoptosis in response to IFNγ stimulation. STAT1 positively regulates the expression of gene encoding many antiproliferative and proapoptotic molecules such as IFNγ regulatory factor 1 (IRF-1), 2,[25][26][27] …”

Mnk kinases in cytokine signaling and regulation of cytokine responses

“…In the case of IFNγ, Erk regulates IFNγ-dependent proteosomal degradatation of PPARδ [94] and enhances IFNγ regulated transcription by CCAAT-enhancer binding protein-β (C/CEBP-β) [88]. In addition, inhibition of Erk1 can partially reverse the antiproliferative effects of IFNγ on oligodendroglial progenitor cells [95]. …”