RT Journal Article SR Electronic T1 Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) Induces Astrocyte Proliferation through the Activation of Transforming Growth Factor (TGF)- α/epidermal Growth Factor Receptor (EGFR) Signaling Pathway JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.112.079608 DO 10.1124/mol.112.079608 A1 Estelle Rousselet A1 Sabine Traver A1 Yann Monnet A1 Aline Perrin A1 Nathalie Mandjee A1 Audrey Hild A1 Etienne C. Hirsch A1 Timothy S. Zheng A1 Stephane Hunot YR 2012 UL http://molpharm.aspetjournals.org/content/early/2012/08/21/mol.112.079608.abstract AB 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 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 to 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 the stimulation of the transforming growth factor alpha (TGF-α) and of the EGFR signaling pathway through ERK and p38 MAPK 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 mechanism may allow novel approaches of human pathologies associated with astrocyte proliferation.