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Université de Caen, CNRS UMR 6551, IFR 47, bd H. Becquerel, BP 5229, 14074 Caen Cedex, France; and
* Max-Planck-Institut, für physiologische und klinische Forschung, D-61231 Bad-Nauheim, Germany
1Correspondence: Université de CAEN-CNRS UMR 6551, Laboratoire de Neurosciences, BP 5229, 14074 Caen Cedex, France. E-mail: d.vivien{at}neuro.unicaen.fr
The tissue type plasminogen activator (t-PA) is a serine protease that is involved in neuronal plasticity and cell death induced by excitotoxins and ischemia in the brain. t-PA activity in the central nervous system is regulated through the activation of serine protease inhibitors (serpins) such as the plasminogen activator inhibitor (PAI-1), the protease nexin-1 (PN-1), and neuroserpin (NSP). Recently we demonstrated in vitro that PAI-1 produced by astrocytes mediates the neuroprotective effect of the transforming growth factor-ß1 (TGF-ß1) in NMDA-induced neuronal cell death. To investigate whether serpins may be involved in neuronal cell death after cerebral ischemia, we determined, by using semiquantitative RT-PCR and in situ hybridization, that focal cerebral ischemia in mice induced a dramatic overexpression of PAI-1 without any effect on PN-1, NSP, or t-PA. Then we showed that although the expression of PAI-1 is restricted to astrocytes, PN-1, NSP, and t-PA are expressed in both neurons and astrocytes. Moreover, by using semiquantitative RT-PCR and Western blotting, we observed that only the expression of PAI-1 was modulated by TGF-ß1 treatment via a TGF-ß-inducible element contained in the PAI-1 promoter (CAGA box). Finally, we compared the specificity of TGF-ß1 action with other members of the TGF-ß family by using luciferase reporter genes. These data show that TGF-ß and activin were able to induce the overexpression of PAI-1 in astrocytes, but that bone morphogenetic proteins, glial cell line-derived neutrophic factor, and neurturin did not. These results provide new insights into the regulation of the serpins/t-PA axis and the mechanism by which TGF-ß may be neuroprotective.—Docagne, F., Nicole, O., Marti, H. H., MacKenzie, E. T., Buisson, A., Vivien, D. Transforming growth factor-ß1 as a regulator of the serpins/t-PA axis in cerebral ischemia.
Key Words: TGF-ß • plasminogen activator • neuroserpin • NTN
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