TRANSFORMING GROWTH-FACTOR BETA-INDUCED TOLERANCE TO CADMIUM CYTOTOXICITY IN CULTURED VASCULAR ENDOTHELIAL-CELLS

We investigated whether or not transforming growth factor beta (TGFP beta) affects the sensitivity to cadmium of bovine aortic endothelial cell in a culture system. Cadmium cytotoxicity was evaluated by [H-3]adenine release assay. It was found that pretreatment with recombinant human TGF beta 1 (rhTGF beta 1) 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-l beta and -6; rhTGF beta 1 was the most potent inducer, rhTGF beta 1 failed to induce the tolerance in the presence of anti-rhTGF beta 1 antibody. Pretreatment with the antibody alone caused a significantly sensitive response to cadmium, suggesting that endogenous TGF beta 1 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 rhTGF beta 1. 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 rhTGF beta 1. It was concluded that rhTGF beta 1 induces a tolerance to cadmium in cultured endothelial cells, caused by a decrease in the cadmium accumulation in the particulate fraction of the cells. TGF beta 1 may serve as a protective factor against cadmium cytotoxicity in vascular endothelial cells.