HYDROGEN-PEROXIDE (H2O2) INCREASES THE STEADY-STATE MESSENGER-RNA LEVELS OF COLLAGENASE MMP-1 IN HUMAN DERMAL FIBROBLASTS/

Reactive oxygen species (ROS) have been shown to be important messenge r molecules in the induction of several genes. In human dermal fibrobl asts the herbicide paraquat (PQ(2+)) was used to induce intracellular oxidative stress that was modulated by the inhibition of copper, zinc superoxide dismutase (Cu,ZnSOD), glutathione peroxidase (GSHPx), catal ase, and blocking of the Fenton reaction. Interstitial collagenase (MM P-1) mRNA increased time dependently for up to 72 h following paraquat treatment. A correlation with the translation of MMP-1 could, however , only be detected up to 24 h, indicating an uncoupling of transcripti on and translation. Interleukin-1 alpha and beta mRNA showed two peaks at 6 h and 72 h. The inhibition of catalase by aminotriazol (ATZ), in hibition of GSHPx by buthionine sulfoximine (BSO), and blocking the Fe nton reaction by the iron chelator desferrioxamine (DFO) in concert le d to an increase in steady-state MMP-1 mRNA levels, possibly dependent on intracellular H2O2 increase. This combined treatment potentiated M MP-1 mRNA induction up to 6.5-fold compared to paraquat treated contro ls. Furthermore, exogenously added H2O2 caused an increase in MMP-1 mR NA levels. In contrast, inhibition of Cu,ZnSOD by diethyldithiocarbama te (DDC), leading to diminished H2O2 production from O-2(.-), decrease d MMP-1 mRNA induction. Collectively, our data provide evidence that H 2O2 is an important intermediate in the downstream signalling pathway finally leading to the induction of increased steady state MMP-1 mRNA levels. The synthesis of MMPs may contribute to connective tissue dama ge in vivo related to photoaging, inflammatory diseases, and tumor inv asion. Copyright (C) 1996 Elsevier Science Inc.