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 inhibitory action of TNFalpha (tumor necrosis factor alpha) on LH/hCG-stimulated testosterone formation. By using cultured porcine Leydig cells as a model, TNFalpha 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 TNFalpha 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 TNFalpha, respectively. Maximal inhibitory effects of TNFalpha on StAR messenger RNA and protein levels were obtained after 48 h of treatment. Additionally, the presence of TNFalpha 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.
Mauduit
C
C
INSERM U407, Centre Hospitalier Lyon-Sud, Pierre Bénite, France. mauduit@lsgrisn1.univ-lyon1.fr
Gasnier
F
F
Rey
C
C
Chauvin
M A
MA
Stocco
D M
DM
Louisot
P
P
Benahmed
M
M
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D006801:Humans; D007985:Leydig Cells / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000494:pharmacology; D008297:Male; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013552:Swine; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D000098682:Steroidogenic Acute Regulatory Protein
D006063:Chorionic Gonadotropin; D010750:Phosphoproteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; D007986:Luteinizing Hormone; D002784:Cholesterol