Regulation of astrocyte GFAP expression by TGF-beta1 and FGF-2.

Astrocytes play a critical role in the development of the CNS and its response to injury and disease. A key indicator of astrocyte activation is the increased accumulation of intermediate filaments composed of glial fibrillary acidic protein (GFAP). Treatment of astrocytes in vitro with transforming growth factor-beta1 (TGF-beta1) produced little morphological change, but resulted in a significant increase in GFAP mRNA and protein. Treatment with basic fibroblast growth factor (FGF-2) produced a dramatic change from a polygonal to a stellate morphology, and resulted in a significant decrease in GFAP mRNA and protein. FGF-2 also inhibited the TGF-beta1-mediated increase in GFAP mRNA and protein. Cycloheximide did not block the effects of TGF-beta1 or FGF-2 on GFAP mRNA levels, but blocked the inhibitory effects of FGF-2 on the TGF-beta1-mediated increase in GFAP expression. All effects of FGF-2 were blocked by co-incubation with 5'-methylthioadenosine, a specific inhibitor of FGF-2-induced tyrosine kinase activity and FGF receptor (FGFR) autophosphorylation. We also examined astrocyte expression of FGFR, and demonstrate the presence of FGFR 1 and 2, and lower levels of FGFR 3. Our results demonstrate that TGF-beta1 and FGF-2 cause differential effects on the astrocyte cytoskeleton and morphology, suggesting an uncoupling of process outgrowth from GFAP synthesis.