Glutathione suppresses TGF-β-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
- 1 November 2007
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Lung Cellular and Molecular Physiology
- Vol. 293 (5), L1281-L1292
- https://doi.org/10.1152/ajplung.00128.2007
Abstract
Transforming growth factor (TGF)-β 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-β 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-β-induced collagen accumulation by blocking PAI-1 expression and enhancing collagen degradation. In the present study, we demonstrate that GSH blocks TGF-β-induced PAI-1 promoter activity in NIH/3T3 cells, which is associated with an inhibition of TGF-β-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-β-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-β-induced PAI-1 promoter activity and inhibit TGF-β-induced expression of endogenous PAI-1. Furthermore, we show that GSH reduces TGF-β-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-β-induced p38 and JNK phosphorylation as well as PAI-1 gene expression. In composite, these findings suggest that GSH inhibits TGF-β-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.This publication has 51 references indexed in Scilit:
- Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-β: implications for carcinogenesisOncogene, 2005
- Inhaled glutathione decreases PGE2 and increases lymphocytes in cystic fibrosis lungsFree Radical Biology & Medicine, 2005
- Role of Rho/ROCK and p38 MAP Kinase Pathways in Transforming Growth Factor-β-mediated Smad-dependent Growth Inhibition of Human Breast Carcinoma Cells in VivoOnline Journal of Public Health Informatics, 2005
- Plasminogen activator inhibitor type‐1 gene expression and induced migration in TGF‐β1‐stimulated smooth muscle cells is pp60c‐src/MEK‐dependentJournal of Cellular Physiology, 2004
- Reactive oxygen species mediate TGF-β1-induced plasminogen activator inhibitor-1 upregulation in mesangial cellsBiochemical and Biophysical Research Communications, 2003
- Mechanisms of TGF-β Signaling from Cell Membrane to the NucleusCell, 2003
- Ras‐dependent and ‐independent regulation of reactive oxygen species by mitogenic growth factors and TGF‐β1The FASEB Journal, 2000
- Role of Transforming Growth Factor β in Human DiseaseThe New England Journal of Medicine, 2000
- A mechanism of repression of TGFbeta / Smad signaling by oncogenic RasGenes & Development, 1999
- A common response element mediates differential effects of phorbol esters and forskolin on type‐1 plasminogen activator inhibitor gene expression in human breast carcinoma cellsJBIC Journal of Biological Inorganic Chemistry, 1994