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Interleukin-1 Inhibits Cholesterol Side-Chain Cleavage Cytochrome P450 Expression in Primary Cultures of Leydig Cells^*

Medical and Research Services, W.J.B. Dorn Veterans Hospital Columbia, South Carolina 29201
the Department of Medicine, University of South Carolina School of Medicine Columbia, South Carolina 29201

Address requests for reprints to: Tu Lin, M.D., Medical Service, W.J.B. Dorn Veterans Hospital, Columbia, South Carolina 29201.

Abstract

Interleukin-1 (IL-1) is a potent inhibitor of Leydig cell function. We have reported that IL-1 inhibited hCG-induced cAMP and testosterone formation. In the present study we evaluated the effect of IL-1 on Leydig cell cholesterol sidechain cleavage cytochrome P450 (P450scc) mRNA levels. P450scc is the rate-limiting enzyme for Leydig cell steroidogenesis. Highly purified Leydig cells were prepared from adult Sprague-Dawley male rats (55–65 day-old) using the combination of elutriation and Percoll gradient. Purified Leydig cells were then cultured with or without IL-β (1–100 ng/ml) and recombinant human monocyte-derived IL-1 receptor antagonist (250 ng/ml) for 24 h. hCG (10 ng/ml), 8-bromo-cAMP (0.1 mM), or 4β-phorbol 12β-myristate 13-acetate was then added, and cultures were continued for an additional 6 h. P450scc mRNA levels of Leydig cells were very low to undetectable after 24 h in culture and could be stimulated by the addition of either hCG (10 ng/ml) or 8-bromo-cAMP (0.1 mM), but the addition of 4β-phorbol 12β-myristate 13-acetate had no effect. P450scc mRNA levels increased as early as 2 h after the addition of hCG. Furthermore, cycloheximide (1 µg/ml) markedly blocked hCG-induced P450scc mRNA expression. This indicates that synthesis of a labile new protein(s) is required for the induction of P450scc mRNA by hCG. IL-1/3 inhibited hCG-stimulated testosterone formation and P450scc mRNA expression in a dose-dependent manner. The inhibitory effects of IL-1/3 could be reversed by the concomitant addition of IL-1 receptor antagonist. Our results suggest that P450scc mRNA levels of Leydig cells are modulated by IL-1. This may be one mechanism that could explain the inhibitory effects of IL-1 on Leydig cell steroidogenesis. (Endocrinology 129: 1305–1311, 1991)

Footnotes

^* This work was supported by NIH Grant 1RO1-HD-25641–03 and the Department of Veterans Affairs Medical Research Fund (to T.L.).

Received April 12, 1991.

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