Inhibition of p70S6 Kinase during Transforming Growth Factor-β1/Vitamin D3-induced Monocyte Differentiation of HL-60 Cells Allows Tumor Necrosis Factor-α to Stimulate Plasminogen Activator Inhibitor-1 Synthesis

Abstract

We investigated intracellular mechanisms involved in the up-regulation of plasminogen activator inhibitor I (PAI-1) synthesis by human recombinant tumor necrosis factor-␣ (TNF) during monocyte differentiation of HL-60 cells triggered by the transforming growth factor-␤1/ vitamin D 3 (TGF/D3) mixture. TGF/D3-treated cells expressed surface monocytic markers and produced noticeable amounts of PAI-1 but stopped to proliferate. A reduced p70 S6 kinase (p70 S6K ) phosphorylation was also observed and, in this situation, TNF dramatically enhanced PAI-1 synthesis. Similarly, TNF significantly up-regulated PAI-1 synthesis when p70 S6K phosphorylation was inhibited by rapamycin. This phenomenon was not due to a general decrease in protein synthesis but involved the activation of gene transcription rather than PAI-1 mRNA stabilization. The level of the transcriptional regulator factor E2F1, a repressor of PAI-1 gene expression, was shown to be down-modulated in TGF/D3-as well as in rapamycin-treated cells. Furthermore, the apoptotic effect of TNF in HL-60 cells appeared to be prevented by the addition of either TGF/D3 or rapamycin. In conclusion, these results indicate that inhibition of p70 S6K phosphorylation during TGF/D3-induced monocyte differentiation of HL-60 cells is a determinant factor that allows TNF to exert its up-regulating effect on PAI-1 synthesis while protecting cells from apoptosis.

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