Up-regulation of mitochondrial peripheral benzodiazepine receptor expression by tumor necrosis factor alpha in testicular Leydig cells - Possible involvement in cell survival

Porcine Leydig cells in primary cultures are resistant to tumor necrosis fa ctor alpha (TNF alpha) cytotoxicity. Here we report that these cells can be rendered sensitive to TNF alpha killing by treatment with the translationa l inhibitor cycloheximide, suggesting the existence of proteins that can su ppress the death stimulus induced by the cytokine. In search of these cytop rotective proteins, we focused on the constituents of the mitochondrial per meability transition pore (PT pore), whose opening has been shown to play a critical role in the TNF alpha -mediated death pathway. We found that TNF alpha up-regulated mRNA and protein expression of the mitochondrial periphe ral benzodiazepine receptor (PBR), an outer membrane-derived constituent of the pore. A strong correlation was established between the resistance of t he cells to TNF alpha killing and the density of PER-binding sites. Concomi tantly, TNF alpha down-regulated Bcl-2 mRNA and protein expression. As Bcl- 2 has been shown to be an endogenous inhibitor of the PT pore, we hypothesi ze that the TNF alpha -induced up-regulation of PER expression may compensa te for the decrease in Bcl-2 levels to prevent the opening of the PT pore. (C) 2000 Elsevier Science Inc.