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Interferon- Inhibits the Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid Expression and Protein Levels in Primary Cultures of Rat Leydig Cells¹

Medical and Research Services, W. J. B. Dorn Veterans Affairs Medical Center, and the Department of Medicine, University of South Carolina School of Medicine (T.L., J.H., D.W.), Columbia, South Carolina 29208; and Department of Cell Biology and Biochemistry, Texas Tech University School of Medicine Health Sciences Center (D.M.S.), Lubbock, Texas 79430

Address all correspondence and requests for reprints to: Tu Lin, M.D., Department of Medicine, University of South Carolina School of Medicine, Medical Library Building, Suite 316, Columbia, South Carolina 29208.

Interferon- (IFN) is an immunomodulating cytokine that has profound effects on reproductive function. IFN inhibits steroidogenesis both in vivo and in vitro. The mechanism by which IFN inhibits Leydig cell steroidogenesis remains unclear. In the present study, we evaluated the effect of IFN on the expression and regulation of the steroidogenic acute regulatory protein (StAR) gene in primary cultures of rat Leydig cells. StAR facilitates the efficient production of steroid hormone by regulating the translocation of cholesterol from the outer to the inner mitochondrial membrane, the site of the cytochrome P450 side-chain cleavage (P450scc) enzyme system that converts cholesterol to pregnenolone. IFN inhibited hCG-induced StAR messenger RNA (mRNA) levels in a dose-dependent manner. The addition of IFN in a concentration of 500 U/ml decreased hCG-induced 3.8- and 1.7-kilobase StAR mRNA by 78% and 70%, respectively. IFN also reduced hCG-stimulated P450scc mRNA levels by 69%. The inhibitory effects of IFN on StAR mRNA levels were confirmed by ribonuclease protection assay. As early as 12 h after the addition of IFN, hCG-induced StAR mRNA levels decreased by more than 44%. To evaluate the effects of IFN on StAR protein levels, Western blot analyses were performed. hCG in a concentration of 10 ng/ml increased StAR protein by 5.6-fold. Treatment of Leydig cells with IFN (500 U/ml) decreased hCG-induced StAR protein by 44%. In contrast, interleukin-1 and murine tumor necrosis factor- reduced hCG-induced P450scc mRNA expression without inhibiting StAR mRNA or protein levels. In conclusion, IFN inhibits Leydig cell steroidogenesis by down-regulating StAR gene expression and protein production.

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