MEK-ERK signaling is involved in interferon-gamma-induced death of oligodendroglial progenitor cells.
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-gamma (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.
Horiuchi
Makoto
M
Department of Neurology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
Itoh
Aki
A
Pleasure
David
D
Itoh
Takayuki
T
D000328:Adult; D000818:Animals; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D017931:DNA Primers; D003711:Demyelinating Diseases / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D003470:Culture Media; D017931:DNA Primers; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D007608:Kainic Acid