Abstract
Previous studies indicate that astrocytes are the brain cells that express acidic fibroblast growth factor (aFGF) and that the expression is increased upon activation. However, there has been no study investigating the significance of this phenomenon. Here we report that aFGF treatment of IFNγ-stimulated human astrocytes, and LPS/IFNγ-stimulated human microglia, enhances their secretion of inflammatory cytokines and other materials toxic to human neuroblastoma SH-SY5Y cells. The mechanism of aFGF enhancement involves stimulation of the receptor FGFR2 IIIb. We show by RT-PCR that this receptor, but not other FGF receptors, is robustly expressed by astrocytes and microglia. We establish by Western blotting, and immunohistochemistry on postmortem human brain tissue that the FGFR2 IIIb protein is expressed by both of these glial cell types. We blocked the inflammatory stimulant action of aFGF by transfecting microglia and astrocytes with a small inhibitory RNA (siRNA) to FGFR2 IIIb as well as by removal of aFGF using an anti-aFGF antibody. Treatment with bFGF in combination with the stimulants was without effect, but together with aFGF, it partially counteracted the action of aFGF, indicating that it may be a weak antagonist of FGFR2 IIIb. The inflammatory effect was also attenuated by treatment with inhibitors of protein kinase C, Src tyrosine kinase, and MEK-1/2 indicating the involvement of these intracellular pathways. Our data suggest that inhibition of expression or release of aFGF could have therapeutic potential by inhibiting inflammation in neurodegenerative diseases such as Alzheimer disease where many neuroinflammatory molecules are prominently expressed.
Highlights
A previous study indicates that activated astrocytes increased expression of acidic fibroblast growth factor (aFGF)
We investigated whether Src tyrosine kinase, protein kinase C (PKC), and MEK-1/2 kinase are downstream molecules activated by aFGFFGFR2 IIIb coupling
In the present study we demonstrated that aFGF enhanced the activity of inflammatory stimulation of astrocytes, microglia, and their surrogate cell lines
Summary
A previous study indicates that activated astrocytes increased expression of aFGF. We investigated the significance of this phenomenon. Previous studies indicate that astrocytes are the brain cells that express acidic fibroblast growth factor (aFGF) and that the expression is increased upon activation. Activation occurs by dimerization of the transmembrane receptors upon binding of the FGF ligand This is followed by autophosphorylation of a number of tyrosine residues, some of which can act as recruitment sites for various effecter downstream molecules such as phospholipase C␥1 and FGFR substrate 2␣. To investigate the significance of this phenomenon, we studied the in vitro effects of aFGF on cultured human astrocytes and microglia, as well as on their surrogate U373 and THP-1 cell lines. We found that aFGF potentiates the inflammatory stimulant effects of LPS and IFN␥ This is due to activation of FGFR2 IIIb, the splicing variant of FGFR2, which is expressed on astrocytes, microglia, and their surrogate THP-1 and U373 cell lines.
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