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Glutathione suppresses TGF--induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter

¹Department of Environmental Health Sciences, School of Public Health, ²Department of Anesthesiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; ³School of Natural Sciences, University of California Merced, Merced, California; and ⁴Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 31 March 2007 ; accepted in final form 14 September 2007

Transforming growth factor (TGF)- upregulates plasminogen activator inhibitor type 1 (PAI-1) in a variety of cell types, and PAI-1 is considered to be an essential factor for the development of fibrosis. Our previous studies demonstrated that TGF- decreased intracellular glutathione (GSH) content in murine embryonic fibroblasts (NIH/3T3 cells), whereas treatment of the cells with GSH, which restored intracellular GSH concentration, inhibited TGF--induced collagen accumulation by blocking PAI-1 expression and enhancing collagen degradation. In the present study, we demonstrate that GSH blocks TGF--induced PAI-1 promoter activity in NIH/3T3 cells, which is associated with an inhibition of TGF--induced JNK and p38 phosphorylation. Interestingly, although exogenous GSH does not affect phosphorylation and/or nuclear translocation of Smad2/3 and Smad4, it completely eliminates TGF--induced binding of transcription factors to not only AP-1 and SP-1 but also Smad cis elements in the PAI-1 promoter. Decoy oligonucleotides (ODN) studies further demonstrate that AP-1, SP-1, and Smad ODNs abrogate the inhibitory effect of GSH on TGF--induced PAI-1 promoter activity and inhibit TGF--induced expression of endogenous PAI-1. Furthermore, we show that GSH reduces TGF--stimulated reactive oxygen species (ROS) signal. Blocking ROS production with diphenyleneiodonium or scavenging ROS with a superoxide dismutase and catalase mimetic MnTBaP dramatically reduces TGF--induced p38 and JNK phosphorylation as well as PAI-1 gene expression. In composite, these findings suggest that GSH inhibits TGF--stimulated PAI-1 expression in fibroblasts by blocking the JNK/p38 pathway, probably by reducing ROS, which leads to an inhibition of the binding of transcription factors to the AP-1, SP-1, and Smad cis elements in the PAI-1 promoter.

transforming growth factor-; plasminogen activator inhibitor-1; mitogen-activated protein kinase

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