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Journal of Andrology, Vol 13, Issue 5 437-443, Copyright © 1992 by The American Society of Andrology

JOURNAL ARTICLE

Direct and indirect effects of murine interleukin-2, gamma interferon, and tumor necrosis factor on testosterone synthesis in mouse Leydig cells

A. W. Meikle, J. C. Cardoso de Sousa, N. Dacosta, D. K. Bishop and W. E. Samlowski
Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City.

It was recently observed that treatment of patients with a high dosage of human interleukin (IL-2) resulted in suppression of plasma concentrations of testosterone. A murine model was developed to assess the direct and indirect effects of murine IL-2 and the secondarily released cytokines, gamma interferon (INF gamma), and tumor necrosis factor (TNF alpha), on testosterone production in isolated Leydig cells. Pretreatment for 24 hours with IL-2 (100 to 500 IU/ml) or INF gamma (100 to 1000 IU/ml) significantly decreased testosterone production in response to luteinizing hormone (LH; P < 0.02 and 0.005, respectively). The combinations of INF gamma with either TNF alpha or IL-2 produced enhanced suppressive effects on Leydig cell testosterone production. Steroidogenic precursors (22-hydroxycholesterol, 17 alpha-hydroxypregnenolone, and dehydroepiandrosterone) restored testosterone secretion to control levels after preincubation with INF gamma or TNF alpha. In contrast, the inhibition of testosterone synthesis produced by either IL-2 or INF gamma plus TNF alpha could be reversed by 17 alpha-hydroxypregnenolone and dehydroepiandrosterone, but not by 22-hydroxycholesterol (P < 0.01). Dibutyryl cyclic adenosine monophosphate was also ineffective in reversing the inhibitory effects of these cytokines on synthesis. Although IL-2 directly inhibited synthesis in isolated Leydig cells, it stimulated testosterone production (P < 0.005) in minced murine testes. This suggests that IL-2 releases regulatory factors from other cells that were able to overcome the direct inhibitory effect of IL-2. This stimulatory effect was not caused by INF gamma and TNF alpha because INF gamma alone or with TNF alpha inhibited (P < 0.005) testosterone production in minced testes.(ABSTRACT TRUNCATED AT 250 WORDS)


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Copyright © 1992 by The American Society of Andrology.