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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1319-1324.
Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-04-1015.
Submitted April 3, 2003
Accepted October 1, 2003
Thymosin  4 induces the synthesis of plasminogen activator inhibitor-1 in cultured endothelial cells and increases its extracellular expression
Khalid N I Al-Nedawi, Malgorzata Czyz, Radoslaw Bednarek, Janusz Szemraj, Maria Swiatkowska, Aleksandra Cierniewska-Cieslak, Janina Wyczolkowska, and Czeslaw S Cierniewski*
Center for Medical Biology and Microbiology, Polish Academy of Sciences, Lodz, Poland; Department of Molecular and Medical Biophysics, Medical University, Lodz, Poland
Department of Medicinal Chemistry, Medical University, Lodz, Poland
Department of Biochemistry, Medical University, Lodz, Poland
* Corresponding author; email: cciern{at}zdn.am.lodz.pl.
Thymosin  4 (T4), a 4.9 kDa polypeptide primarily known as a main G-actin sequestering peptide, is present in high concentrations in various cells and in the circulation. We have found that T4 upregulates the expression of PAI-1 in endothelial cells measured both at the level of mRNA and protein synthesis. This effect seems to be cell specific and was not observed when other cells such as human fibroblasts, PC3, and U937 were tested. T4 significantly activated the PAI-1 promoter in EA. hy 926 cells transiently transfected either with plasmid p800LUC containing the PAI-1 promoter fragment (-800 to +71), or the PAI-1 promoter linked with GFP. T4 mediated upregulation of PAI-1 involved activation of the MAPK cascade. Furthermore, T4 enhanced c-Fos/c-Jun DNA binding activity to the AP-1-like element (59 to 52). The specificity of this binding activity was demonstrated by competition EMSA and after transfection of EA. hy 926 cells with the mutated PAI-1 promoter. Taken together, these data indicate that, in response to T4 stimulation, AP-1 activity increases to enhance PAI-1 transcription through its unique AP-1-like element at 59 to 52 in the PAI-1 promoter.
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