Maturation-dependent modulation of apoptosis in cultured cerebellar granule neurons by cytokines and neurotrophins.
Immature cerebellar granule neurons die by apoptosis within 1 week in vitro unless maintained in depolarizing (high) concentrations of potassium (25 mM K+). Neurons allowed to survive and differentiate in high K+ medium for several days in vitro are still induced to undergo apoptosis when switched back to physiological (low) concentrations of K+ (5 mM). Here we have investigated the effects of various cytokines and growth factors in these two well-defined paradigms of neuronal apoptosis. Tumour necrosis factor-alpha, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin-10 and interleukin-13 delayed apoptosis and prolonged survival of cerebellar granule neurons maintained in low K+ medium. The effect observed required continuous exposure of the cultures to the cytokines and appeared not to involve modulation of Bcl-2 protein expression. Brain-derived neurotrophic factor accelerated neuronal death in low K+ medium. In contrast, when apoptosis of the neurons was precipitated by switching mature high K+ neurons to low K+ medium, neither tumour necrosis factor-alpha, leukaemia inhibitory factor, ciliary neurotrophic factor, interleukin-10 nor interleukin-13 prevented apoptosis. When testing the cytokines and growth factors for their capacity to alter N-methyl-D-aspartate receptor-mediated excitotoxicity of differentiated cerebellar granule neurons, no significant effect was observed. These data appear to define a maturation-dependent modulation of cerebellar granule cell survival by cytokines and neurotrophic factors that are expressed in a developmental pattern in the mammalian brain.
de Luca
A
A
Department of Internal medicine, University Hospital, Zürich, Switzerland.
Weller
M
M
Frei
K
K
Fontana
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D016922:Cellular Senescence; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects*; D003470:Culture Media; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D003470:Culture Media; D016207:Cytokines; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D011188:Potassium