Transforming growth factor beta-induced tolerance to cadmium cytotoxicity in cultured vascular endothelial cells

Abstract

We investigated whether or not transforming growth factor beta (TGFβ1) affects the sensitivity to cadmium of bovine aortic endothelial cell in a culture system. Cadmium cytotoxicity was evaluated by [ 3H]adenine release assay. It was found that pretreatment with recombinant human TGFβ1 (rhTGFβ1) of the confluent cultures resulted in a reduction of cadmium cytotoxicity, suggesting that the cytokine induced a tolerance to cadmium in the cells. Such a tolerance was induced slightly by either recombinant human tumor necrosis factor alpha or recombinant human basic fibroblast growth factor but not by recombinant human interleukin-1 beta and -6; rhTGFβ1 was the most potent inducer. rhTGFβ1 failed to induce the tolerance in the presence of anti-rhTGFβ1 antibody. Pretreatment with the antibody alone caused a significantly sensitive response to cadmium, suggesting that endogenous TGFβ1 can physiologically contribute to protection against cadmium cytotoxicity in endothelial cells. The accumulation of cadmium was increased in the extracellular fraction but significantly decreased in the intracellular fraction of the cells by pretreatment with rhTGFβ1. The cadmium content was significantly decreased in the particulate fraction but not in the cytosol fraction. Gel filtration chromatography of the cytosol fraction revealed that cadmium was bound to high-molecular-weight protein and metallothionein; both peaks were slightly increased by pretreatment with rhTGFβ1. It was concluded that rhTGFβ1 induces a tolerance to cadmium in cultured endothelial cells, caused by a decrease in the cadmium accumulation in the particulate fraction of the cells. TGFβ1 may serve as a protective factor against cadmium cytotoxicity in vascular endothelial cells.