Regulation of plasminogen activator inhibitor-1 mRNA accumulation by basic fibroblast growth factor and transforming growth factor-β1 in cultured rat astrocytes

Abstract

The effects of transforming growth factor-β1 (TGF-β1) and basic fibroblast growth factor (bFGF) were examined on the accumulation of plasminogen activator inhibitor-1 (PAI-1) mRNA in astrocytes in vitro. Both cytokines stimulated PAI-1 mRNA expression transiently with a maximal fivefold (bFGF) and 30-fold (TGF-β1) at 4 h, decreasing to basal levels within 32 h. EC50 values were 1.4 nM for bFGF and 6.7 pM for TGF-β1 on PAI-1 mRNA accumulation. A twofold increase in content of tPA mRNA was observed with bFGF but not with TGF-β1. The action of TGF-β1 on PAI-1 mRNA was inhibited by cycloheximide, indicating a requirement for de novo protein synthesis. In contrast, cycloheximide potentiated the action of bFGF. Nuclear run-on assays showed that bFGF, but not TGF-β1, stimulated astrocytic PAI-1 gene transcription. Thus, TGF-β1 predominantly uses posttranscriptional mechanisms to raise the level of PAI-1 mRNA in astrocytes, whereas bFGF acts at both the transcriptional and posttranscriptional levels. The data reveal differences in the mechanisms underlying the regulation of PAI-1 mRNA levels by TGF-β1 in astrocytes compared with other cells. The action of TGF-β1 and bFGF on the plasminogen activator system in astrocytes might be involved in the cellular events accompanying glial activation following injury of the CNS.