Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta1.
Serine proteases play a key role in the fundamental biology of the central nervous system (CNS), and recent data suggest their involvement in the pathophysiology of neurodegenerative diseases. Little is known about the physiological regulation of these proteases in the CNS. Among the multiple growth factors present in the brain, transforming growth factor beta1 (TGF-beta1) has been described as an injury-related growth factor. However, its beneficial or deleterious role remains unclear. In the present study, we investigated the influence of TGF-beta1 in apoptosis and necrosis, two mechanisms involved in ischemic neuronal death. We show that TGF-beta1 exerts a neuroprotective role restricted to necrosis induced by N-methyl-D-aspartate. This effect is observable only in the obligatory presence of TGF-beta1-responsive astrocytes. We demonstrate that this neuroprotective activity is mediated through an up-regulation of a serine protease inhibitor (PAI-1) in astrocytes. These results underline the involvement of serine proteases and extracellular matrix components such as the PAI-1/t-PA axis in the excitotoxic cascade. Moreover, regardless of the underlying mechanisms of t-PA involvement in excitotoxic injury, our observations might warn against the use of tissular plasminogen activator as an alternative therapy for the treatment of hypoxic-ischemic injury in the brain.
Buisson
A
A
Université de CAEN, CNRS UMR 6551, Laboratoire de Neurosciences, bd H. Becquerel, BP 5229, 14074 CAEN Cedex, France.
Nicole
O
O
Docagne
F
F
Sartelet
H
H
Mackenzie
E T
ET
Vivien
D
D
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015842:Serine Proteinase Inhibitors / Q000096:biosynthesis*; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
D018696:Neuroprotective Agents; D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D015842:Serine Proteinase Inhibitors; D016212:Transforming Growth Factor beta; D016202:N-Methylaspartate; D010959:Tissue Plasminogen Activator