Title: AP-1-dependent induction of plasminogen activator inhibitor-1 by nickel does not require reactive oxygen.
Authors: Andrew, A S; Klei, L R; Barchowsky, A
Published In Am J Physiol Lung Cell Mol Physiol, (2001 Sep)
Abstract: Inhalation of nickel dust has been associated with an increased incidence of pulmonary fibrosis. Nickel may promote fibrosis by transcriptionally activating plasminogen activator inhibitor (PAI)-1 and inhibiting fibrinolysis. The current studies examined whether nickel stimulated the PAI-1 promoter though an oxidant-sensitive activator protein (AP)-1 signaling pathway. Addition of nickel to BEAS-2B human airway epithelial cells stimulated intracellular oxidation, induced c-Jun and c-Fos mRNA levels, increased phospho- and total c-Jun protein levels, and elevated PAI-1 mRNA levels over a 24-h time course. Pretreatment of the cells with antioxidants did not affect increased c-Jun protein or PAI-1 mRNA levels. Expression of the dominant negative inhibitor of AP-1, TAM67, prevented nickel-stimulated AP-1 DNA binding, AP-1-luciferase reporter construct activity, and PAI-1 mRNA levels. Overexpression of c-Jun, however, failed to induce the AP-1 luciferase reporter construct or PAI-1 mRNA levels. These data indicated that nickel activated AP-1 through an oxidant-independent pathway and that basal AP-1 is necessary for nickel-induced expression of PAI-1.
PubMed ID: 11504688
MeSH Terms: Cell Line; DNA-Binding Proteins/physiology; DNA/antagonists & inhibitors; DNA/metabolism; Gene Expression Regulation/physiology; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Nickel/antagonists & inhibitors; Nickel/pharmacology*; Nuclear Proteins/physiology; Phosphoproteins/metabolism; Plasminogen Activator Inhibitor 1/genetics*; Proto-Oncogene Proteins c-fos/genetics; Proto-Oncogene Proteins c-jun/genetics; RNA, Messenger/antagonists & inhibitors; RNA, Messenger/metabolism; Reactive Oxygen Species/metabolism; Transcription Factor AP-1/antagonists & inhibitors; Transcription Factor AP-1/genetics; Transcription Factor AP-1/physiology*; Transcription Factors*; Transcriptional Activation/drug effects