Tumor necrosis factor-like weak inducer of apoptosis induces astrocyte proliferation through the activation of transforming-growth factor-α/epidermal growth factor receptor signaling pathway.

Estelle Rousselet, Sabine Traver, Yann Monnet, Aline Perrin, Nathalie Mandjee, Audrey Hild, Etienne C Hirsch, Timothy S Zheng, Stéphane Hunot

Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, Experimental Therapeutics of Neurodegeneration, Paris, France.

Molecular pharmacology 2012 Nov

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Reactive astrogliosis is beneficial in many aspects; however, it is also detrimental in some pathological states such as the development of lethal brain tumors. It is therefore crucial to understand the mechanisms regulating astrocyte proliferation. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor family, was shown to stimulate astrocyte proliferation in vitro. Herein, we further characterize the mitogenic potential of TWEAK on central nervous system cells. Among these cells, astrocytes express the highest level of TWEAK and Fn14 transcripts, suggesting that they are particularly sensitive to TWEAK stimulation. Using in vitro model systems, we found that TWEAK was as potent as epidermal growth factor (EGF) (a prototypical astrocyte mitogen) in mediating astrocyte proliferation. However, its mitogenic activity was delayed compared with that of EGF, suggesting distinct mechanisms of action. Using cell signaling pathway inhibitors, neutralizing antibodies, and protein assays, we further show that the mitogenic activity of TWEAK on primary astrocytes requires stimulation of the transforming growth factor-α (TGF-α) and of the epidermal growth factor receptor (EGFR) signaling pathway through extracellular signal-regulated kinase and p38 mitogen-activated protein kinase activation. In aggregates, our data demonstrate that TWEAK acts as a potent astrocyte mitogen through the induction of a TGF-α/EGFR signaling pathway. We anticipate that description of such a mechanism may allow novel approaches to human pathologies associated with astrocyte proliferation.

Citation

Estelle Rousselet, Sabine Traver, Yann Monnet, Aline Perrin, Nathalie Mandjee, Audrey Hild, Etienne C Hirsch, Timothy S Zheng, Stéphane Hunot. Tumor necrosis factor-like weak inducer of apoptosis induces astrocyte proliferation through the activation of transforming-growth factor-α/epidermal growth factor receptor signaling pathway. Molecular pharmacology. 2012 Nov;82(5):948-57