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Evidence for a Smad-mediated Up-regulation of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 by Transforming Growth Factor Beta

1Schacke W., 2Beck K.-F., 2Pfeilschifter J., 3Koch F., 3Hattenbach L.-O.,
1Johann-Wolfgang-Goethe-Universität, Klinik für Augenheilkunde (Frankfurt/Main)
2Johann-Wolfgang-Goethe-Universität, Pharmazentrum Frankfurt (Frankfurt/Main)
3Johann-Wolfgang-Goethe-Universität, Klinik für Augenheilkunde, Netzhaut- und Glaskörperchirurgie (Frankfurt/Main)

Purpose: We could previously show, that tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), but not urokinase plasminogen activator (u-PA) are upregulated in human retinal glial cells (HRGC) after treatment with transforming growth factor-beta (TGF-beta). In this study we provide evidence, that this upregulation is probably mediated by Smad2.
Method: Cultures of HRGC were treated with TGF-beta and RNA, protein and supernatant was collected for further analysis. Levels of t-PA and PAI-1 mRNA were determined by RT-PCR, whereas the extracellular release of t-PA and PAI-1 protein was measured by enzyme-linked immunosorbent assay. Levels of phosphorylated Smad2 were detected by Western blot analysis.
Results: Treatment of HRGC with TGF-beta resulted in a marked increase of phosphorylated Smad2. This stimulatory effect was inhibited after pretreatment with interferon-gamma (IFN-gamma). Furthermore, we could demonstrate, that IFN-gamma reverses the stimulatory effect of TGF-beta on t-PA mRNA and protein, but not on PAI-1.
Conclusions: The finding that t-PA and PAI-1 synthesis by HRGC is mediated by TGF-beta and its downstream effector Smad2 confirms the importance of the TGF-beta signaling pathway in the regulation of interactions between retinal cells and the extracellular matrix.
Supported by August-Scheidel-Stiftung.