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Tumor Necrosis Factor a Inhibits Gonadotropin Action in Cultured Porcine Leydig Cells: Site(s) of Action^*

INSERM CJF No. 90-08, Groupe de Recherches sur les Communications Cellulaires, Laboratoíre Biochimie, Hôpital Sainte Eugenie, Centre Hospitalier Lyon-Sud Centre Hospitalier Lyon-Sud, 69310
Pierre-Benite and Centre de Radioanalyse, Institut Pasteur 69007 Lyon, France

Address all correspondence and requests for reprints to: Dr. M. Benahmed, Groupe de Recherches sur les Communications Cellulaires, Laboratoire de biochimie, Hôpital Sainte Eugenie, Centre Hospitalier Lyon-Sud 69310 Pierre-Benite, France.

Abstract

In the present study, we have tested the direct effects of tumor necrosis factor- (TNF-) on basal and human (h)CG-stimulated testosterone secretion by cultured purified Leydig cells isolated from immature porcine testes. TNF- reduced (as much as 90% decrease) hCG-stimulated, but not basal testosterone secretion in a dose- and time-dependent manner. The maximal and half-maximal effects were, respectively, 3.75 ng/ml (2.2 x 10^–10 M) and 0.66 ng/ml (3.9 x 10^–11 M) of TNF- after 48 h treatment. TNF- antagonizes the gonadotropin hormonal action by affecting at least two types of biochemical steps. First, TNF- reduced LH/hCG binding to a maximal decrease of 45% obtained with 2 ng/ml of TNF- after 48 h of treatment. TNF- also inhibited (44% decrease) hCG-stimulated cAMP production in optimal conditions (20 ng/ml, 72 h). Second, TNF- significantly (P < 0.001) reduced testosterone secretion stimulated with 8-bromo-cAMP (3 x 10^–3 M) in a similar range (86% decrease) to that observed with the gonadotropin. Such an observation indicates that the antigonadotropic action of the cytokine is exerted in a predominant manner at a step(s) located beyond cAMP formation. Furthermore, incubation of Leydig cells with 22R-hydroxycholesterol (5 µg/ml, 2 h) reversed most of the inhibitory effect of TNF- on androgen production. Indeed, the TNF- (20 ng/ml, 72 h) inhibitory effect on testosterone production was limited to about 20% (P < 0.03) in Leydig cells supplied with 22R-hydroxycholesterol. Such a moderate effect of the cytokine in the presence of 22R-hydroxycholesterol compared with that observed when androgen secretion was stimulated with the gonadotropin (up to 90% inhibition) indicate that TNF- acts by dramatically reducing cholesterol substrate availability in the mitochondria. Such an effect of TNF-a is directly exerted on Leydig cells since TNF-a receptors (dissociation constant 5.4 x 10^–10 M) are present in primary cultures of purified porcine Leydig cells. Together, the present findings show that in Leydig cells TNF- antagonizes the gonadotropin action on testosterone formation predominantly through a decrease in the availability of cholesterol substrate in the mitochondria. (Endocrinology 129: 2933-2940, 1991)

Footnotes

^* This work was supported by Institut No. National de la Santé et de la Recherche Medicale (INSERM, CJF No. 90-08), Ministére de l’Education Nationale, Fondation pour la Recherche en Hormonologie (FRH No. 699101).

Received June 19, 1991.

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