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

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-␣ (TGF-␣) 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-␣/EGFR signaling pathway. We anticipate that description of such a mechanism may allow novel approaches to human pathologies associated with astrocyte proliferation.

BAFF, APRIL, TWEAK, BCMA, TACI and Fn14 Proteins Are Related to Human Glioma Tumor Grade: Immunohistochemistry and Public Microarray Data Meta-Analysis

“…TWEAK, is present in all kinds of glial cells, and staining intensity follows tumor grade. However, this immunostaining is quite heterogeneous, in accordance with previous data suggesting that TWEAK/Fn14 expression in normal brain displayed a varying intensity, depending on brain topography [41]. This tandem of ligand-receptor further showed an increased expression in MS astrocytes, following the severity and time course of the disease [44], [52]–[54].…”

“…APRIL has been identified in reactive but not in quiescent astrocytes and microglia and is also up-regulated within MS plaques [40]. Finally, TWEAK and its receptor Fn14 expression was identified mainly in astrocytes, but also in microglia, and neurons [41], displaying a variable expression in different normal brain areas. In addition, TWEAK and Fn14 have been found in neurons of the cerebral cortex, caudate nucleus, putamen, substantia nigra, cerebellar Purkinje cells and spinal cord and endothelial cells of medium- and small-caliber blood vessels.…”

The TWEAK‐Fn14 system as a potential drug target

“…Secondly, TWEAK increases the permeability of the BBB in vitro and in vivo by at least two mechanisms, on the one hand by classical NFκB‐mediated induction of the basement degrading MMP9 protease (Polavarapu et al ., ) and on the other hand by stimulating transcellular transport of neutrophils through the interface of astrocytes and endothelial cells (Haile et al ., ). Thirdly, TWEAK‐induced activation of microglia and astrocytes results in the production of proinflammatory cytokines and chemokines (Haile et al ., ) including TGFα, which can act as an autocrine inducer of astrocyte proliferation via EGFR stimulation (Rousselet et al ., ). For example, immunohistochemical analysis of the necrotic core of MACO‐induced ischaemia revealed a strong increase of activated microglia and this was found to been reduced in animals with intracerebroventricular injection of Fn14‐Fc (Yepes et al ., ).…”

A Mechanism for the Upregulation of EGF Receptor Levels in Glioblastomas

“…Here we show that tTG plays an important role in the transformed properties of these cancer cells by having a major influence on EGFR protein levels and signaling activities. The ability of tTG to affect EGFR expression and function has significant implications for brain cancer given that this receptor tyrosine kinase has been shown to trigger mitogenic and survival responses in both normal astrocytes and brain tumor-derived cell lines (Lund-Johansen et al, 1990; Rousselet et al, 2012). Moreover, ectopic expression of the EGFR in normal cell types induces their transformation in a ligand-dependent manner, suggesting that increased signaling by the EGFR plays a critical role in promoting human malignancies (Moscatello et al, 1996).…”