Activin and inhibin have opposite effects on steroid 5-reductase activity in genital skin fibroblasts
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The transforming growth factor β (TGF-β) superfamily includes several closely related peptides including the activins and inhibins. Since we recently reported that TGF-β1 and β2 are potent inducers of steroid 5-reductase (5R), we have now studied the effects of these other peptides using primary cultures of human scrotal skin fibroblasts.
Recombinant human activin A or inhibin A were added to cultured cells (2 × 105 cells) for 2 days in a serum free media and 5R activity was measured by the %-conversion of tracer [3H]-testosterone to dihydrotestosterone (DHT) over a 4-h period.
Activin significantly stimulated 5R activity in a dose related manner (control 3.0 ± 0.4%, activin (1.2 × 10−9 M) 6 ± 0.7%, P < 0.01, (2.4 × 10−9 M) 8.5 ± 0.6%, P < 0.001).
In comparison, androgen (DHT 10−7 M) induction of 5R was 4.7 ± 0.2%, P < 0.05. Combined exposure of fibroblasts to activin (1.2 × 10−9 M) and androgen (10−7 M) did not result in additive or synergistic effect on 5R activity. In contrast, exposure of cells to an androgen (10−7 M) and TGF-β (2 × 10−10 M) led to synergistic effects on 5R activity (control 1.5 ± 0.1%, DHT 2.6 ± 0.2% TGF-β1 4.8 ± 0.5, TGF-β1+DHT 9.2 ± 1.2%).
Finasteride, a 4-aza steroid inhibitor of 5R (10−8 M) inhibited both activin and TGF-β-induced 5R activity suggesting that the type II isoenzyme is induced by these peptides.
Activin mediated 5R activity was abolished by the addition of cycloheximide, consistent with the proposition that enzyme induction requires new protein synthesis.
Recombinant human inhibin alone did not alter basal 5R activity but dose dependently inhibited DHT (10−7 M)-induced 5R activity (control 4.1 ± 0.4%, DHT 7.5 ± 0.7%, DHT + inhibin (0.6 × 10−9 M) 5.7 ± 0.5%, P < 0.05 DHT + inhibin (1.2 × 10−9 M] 4.3 ± 0.2%, P < 0.001).
The effects of activin or inhibin were not associated with changes in cell number or thymidine uptake.
These studies indicate that activin is 100 times more potent on a molar basis than androgen in induction of 5R activity. Although both activin and TGF-β1 induce 5R activity, the actions of the two peptides differ in the presence of an androgen. In contrast, inhibin significantly inhibits androgen induction of 5R. Activin and inhibin, two closely related molecules, potentially play opposite roles in DHT formation in sexual tissue.