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Tumor Necrosis Factor- Inhibits Leydig Cell Steroidogenesis through a Decrease in Steroidogenic Acute Regulatory Protein Expression¹

INSERM U407 (C.M., M.-A.C., M.B.), Centre Hospitalier Lyon-Sud, 69 495 Pierre Bénite cedex, France; INSERM U189 (F.G., C.R., P.L.), Faculté de Médecine Lyon-Sud, BP 12, 69 921 Oullins, France; and Department of Cell Biology and Biochemistry (D.M.S.), Texas Tech University Health Sciences Center, Lubbock, Texas 79430

Address all correspondence and requests for reprints to: Claire Mauduit, INSERM U407, Bât 3B, Centre Hospitalier Lyon-Sud, 69 495 Pierre Bénite cedex, France. E-mail: mauduit{at}lsgrisn1.univ-lyon1.fr

The aim of the present study was to identify the sites of the inhibitory action of TNF (tumor necrosis factor alpha) on LH/hCG-stimulated testosterone formation. By using cultured porcine Leydig cells as a model, TNF was shown to inhibit testosterone secretion when testicular cells were stimulated with hCG but not when incubated with 22R-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 availability to cytochrome P450scc in the mitochondria. Specifically, we report here that TNF reduced in a dose- and time-dependent manner hCG-induced StAR (steroidogenic acute regulatory protein) levels. The maximal and half-maximal effects were obtained with 20 ng/ml (1.2 nM) and 1.6 ng/ml (0.09 nM) of TNF, respectively. Maximal inhibitory effects of TNF on StAR messenger RNA and protein levels were obtained after 48 h of treatment. Additionally, the presence of TNF receptors P55 in terms of protein (identified through cross-linking experiments) and messenger RNA (identified through RT-PCR analysis) suggested that the effects of the cytokine are directly exerted on the testicular steroidogenic cell type.

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