Abstract
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.
Footnotes
This study was supported by Institut National de la Santé et de la Recherche Médicale and the National Parkinson Foundation (Miami, FL). E.R. was supported by a grant from Fondation France Parkinson. E.C.H. and S.H. are investigators at the Centre National de la Recherche Scientifique.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- CNS
- central nervous system
- TWEAK
- tumor necrosis factor-like weak inducer of apoptosis
- TNF
- tumor necrosis factor
- Fn14
- fibroblast growth factor-inducible 14
- TNFR
- tumor necrosis factor receptor
- NF-κB
- nuclear factor κB
- MAPK
- mitogen-activated protein kinase
- TRAF
- tumor necrosis factor receptor-associated factor
- TGF-α
- transforming growth factor-α
- EGFR
- epidermal growth factor receptor
- DMEM
- Dulbecco's modified Eagle's medium
- FCS
- fetal calf serum
- MK-801
- dizocilpine maleate
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- EGF
- epidermal growth factor
- bFGF
- basic fibroblast growth factor
- HB-EGF
- human heparin-binding EGF-like growth factor
- PD98059
- 2′-amino-3′-methoxyflavone
- ERK
- extracellular signal-regulated kinase
- SB203580
- 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
- bis-tris
- 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol
- IκB
- inhibitor of nuclear factor-κB
- GFAP
- glial fibrillary acidic protein.
- Received April 27, 2012.
- Accepted August 13, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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