Interleukin-1 inhibits Leydig cell steroidogenesis without affecting steroidogenic acute regulatory protein messenger ribonucleic acid or protein levels

Abstract

The rate-limiting step of steroidogenesis is the transport of the substrate cholesterol from the outer to the inner mitochondrial membrane which involves a cycloheximide-sensitive newly synthesized protein. A protein believed to carry out this function was recently cloned from MA-10 mouse Leydig tumor cells and named the steroidogenic acute regulatory protein (StAR). In the present study, we evaluated the expression and regulation of StAR in primary cultures of rat Leydig cells. StAR mRNA was expressed in Leydig cells as two major transcripts of 3·8 and 1·7 kb and one minor transcript of 1·2 kb. Induction of StAR mRNA transcripts could be detected as early as 30 min after the addition of human choriogonadotropin (hCG) with peak levels attained between 2 and 4 h. hCG in concentrations of 0·1-10 ng/ml caused a dose-dependent increase in StAR mRNA expression. hCG administered at a dose of 10 ng/ml increased the 3·8 kb StAR mRNA level about 14-fold and the 1·7 kb StAR mRNA level about 13·6-fold. hCG-stimulated StAR mRNA was associated with increased StAR protein levels as determined by immunoblot analysis (a 4·5-fold increase). Murine interleukin-1 (mIL-1 ) at a concentration of 100 ng/ml inhibited hCGinduced cytochrome P450 side-chain cleavage (P450 scc) mRNA expression and testosterone formation almost completely. Interestingly, mIL-1 had no effect on hCGinduced StAR mRNA or protein levels. Furthermore, mIL-1 (10 ng/ml) decreased conversion of (22R)-hydroxycholesterol to testosterone while the conversion of pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone and androstenedione to testosterone were not affected. These results indicate that the major inhibitory effect of IL-1 on Leydig cell function occurs at the level of P450 scc.

The effect of secondary cholestasis on the CD68-positive and CD163-positive macrophage population, cellular proliferation, and apoptosis in rat testis

“…These data indicate that the direct inhibition of Leydig cell function is the primary reason for the decline in androgen levels during systemic inflammation, rather than the inhibition of the hypothalamo-anterior pituitary axis (Gow et al, 2001;O'Bryan et al, 2000). This inhibition is most likely due to the effects of inflammatory cytokines and other mediators on the Leydig cell (Bosmann et al, 1996;Gow et al, 2001;Lin et al, 1998Lin et al, , 1991O'Bryan et al, 2000). A significant increase in the numbers of CD68 + and CD163 + macrophages in the testicular interstitium following CBDL may be due to endotoxemia.…”

INHIBITION OF STEROIDOGENESIS IN LEYDIG CELLS BY EXOGENOUS NITRIC OXIDE OCCURS INDEPENDENTLY OF STEROIDOGENIC ACUTE REGULATORY PROTEIN (StAR) MRNA

“…The transport step is mediated by steroidogenic acute regulatory protein (StAR), which is rapidly synthesized in response to cAMP. StAR mRNA exists in Leydig cells as 2 major transcripts with lengths of 3.8 and 1.7 kB, and one minor transcript of 1.2 kB [18].…”

Importance of abdominal circumference and body mass index values in predicting male hypogonadism – A practical approach

“…Moreover, abundant cytokine production within the fat tissue also inhibits testosterone production through intracellular mechanisms. Alpha tumor necrosis factor (α-TNF), for instance, inhibits steroid production inside Leydig cells, at the intracellular transcription level, whereas interleukine-1 (IL-1) inhibits the cholesterol side-chain cleavage by the p450 cytochrome inside the Leydig cells (15).…”