Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells.
TNF-alpha has been reported to be relevant in stroke-induced neuronal death. However the precise function of TNF-alpha in brain ischemia remains controversial since there are data supporting either a detrimental or a protective effect. Here we show that TNF-alpha is released after oxygen-glucose deprivation (OGD) of cortical cultures and is a major contributor to the apoptotic death observed without affecting the OGD-mediated necrotic cell death. In this paradigm, apoptosis depends on TNF-alpha-induced activation of caspase-8 and -3 without affecting the activation of caspase-9. By using knock-out mice for TNF-alpha receptor 1, we show that the activation of both caspase-3 and -8 by TNF-alpha is mediated by TNF-alpha receptor 1. The pro-apoptotic role of TNF-alpha in OGD is restricted to neurons and microglia, since astrocytes do not express either TNF-alpha or TNF-alpha receptor 1. Altogether, these results show that apoptosis of cortical neurons after OGD is mediated by TNF-alpha/TNF-alpha receptor 1.
Badiola
Nahuai
N
Institut de Neurociencies, Departament de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Spain.
Malagelada
Cristina
C
Llecha
Nuria
N
Hidalgo
Juan
J
Comella
Joan X
JX
Sabriá
Josefa
J
Rodríguez-Alvarez
José
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D053181:Caspase 8; D005947:Glucose