TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS LEYDIG-CELL STEROIDOGENESIS THROUGH A DECREASE IN STEROIDOGENIC ACUTE REGULATORY PROTEIN EXPRESSION

The aim of the present study was to identify the sites of the inhibito ry action of TNF alpha (tumor necrosis factor alpha) on LH/hCG-stimula ted testosterone formation. By using cultured porcine Leydig cells as a model, TNF alpha was shown to inhibit testosterone secretion when te sticular cells were stimulated with hCG but not when incubated with 22 R-hydroxycholesterol (a cholesterol substrate derivative that readily passes through cell and mitochondrial membranes). Such an observation suggested that the cytokine may affect cholesterol transport and/or av ailability to cytochrome P450scc in the mitochondria. Specifically, we report here that TNF alpha reduced in a dose- and time-dependent mann er hCG-induced StAR (steroidogenic acute regulatory protein) levels. T he maximal and half-maximal effects were obtained with 20 ng/ml (1.2 n M) and 1.6 ng/ml (0.09 nM) of TNF alpha, respectively. Maximal inhibit ory effects of TNF alpha on StAR messenger RNA and protein levels were obtained after 48 h of treatment. Additionally, the presence of TNF a lpha receptors P55 in terms of protein (identified through cross-linki ng experiments) and messenger RNA (identified through RT-PCR analysis) suggested that the effects of the cytokine are directly exerted on th e testicular steroidogenic cell type.