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Glutathione regulates transforming growth factor--stimulated collagen production in fibroblasts

¹Department of Environmental Health Sciences, School of Public Health, and ²Department of Medicine and Pathology and ³Department of Anesthesiology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022

Submitted 15 July 2003 ; accepted in final form 29 August 2003

Transforming growth factor- (TGF-) is a potent fibrogenic cytokine. The molecular mechanism underlying TGF- fibrogenesis, however, has not been completely elucidated. In this study, we showed that TGF decreased the intracellular GSH content in murine embryo fibroblasts (NIH 3T3), which was followed by an increase in collagen I mRNA content and collagen protein production. Prevention of GSH depletion with N-acetylcysteine (NAC), GSH, or GSH ester abrogated TGF--stimulated collagen production, whereas a decrease in intracellular GSH content with L-buthionine-S,R-sulfoximine, an inhibitor of de novo GSH synthesis, enhanced TGF--stimulated collagen production. These results suggest that GSH depletion induced by TGF- may mediate TGF--stimulated collagen production. In addition, we showed that TGF- stimulated superoxide production and increased release of H₂O₂ from the cells, whereas GSH ester decreased basal and TGF- + glucose oxidase-stimulated H₂O₂ release. H₂O₂, exogenously added or continuously generated by glucose oxidase, enhanced TGF--stimulated collagen production, whereas suppression of superoxide production by diphenyliodonium, an NAD(P)H oxidase inhibitor, blocked TGF--stimulated collagen production. These data further suggest that reactive oxygen species are involved in TGF--stimulated collagen production and that the effect of GSH depletion on TGF--stimulated collagen production may be mediated by facilitating reactive oxygen species signaling.

glutathione ester; [³H]proline incorporation; collagen I mRNA; reactive oxygen species

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