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Inhibins Differentially Antagonize Activin and Bone Morphogenetic Protein Action in a Mouse Adrenocortical Cell Line

Prince Henry’s Institute, Victoria 3168, Australia

Address all correspondence and requests for reprints to: Paul G. Farnworth, Prince Henry’s Institute, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: paul.farnworth{at}princehenrys.org.

Inhibin, a member of the TGF-ß superfamily, has been proposed to act as an inhibitor of activin and bone morphogenetic protein (BMP) by sequestering their type II receptors in nonsignaling complexes with betaglycan. This mechanism of inhibin action was tested in a mouse adrenocortical (AC) cell line by examining the effects of inhibins A and B on cytochrome P450 17-hydroxylase 17,20-lyase (Cyp17) expression and 17-hydroxylase activity, measured by progesterone 17-hydroxylation, in the absence and presence of activin or BMP isoforms. Cyp17 mRNA endogenously expressed by AC cells was suppressed by activins A and B and BMP-2, -6, and -7, and each ligand accordingly inhibited 17-hydroxyprogesterone production (IC₅₀ of 0.24, 0.27, 0.4, 0.51, and 2.2 nM, respectively). Neither inhibin A nor inhibin B alone affected Cyp17 expression or 17-hydroxyprogesterone production. Both inhibin A and inhibin B blocked the inhibitory actions of activins A and B in AC cells, supporting the antiactivin model of inhibin action. Inhibin A provided more potent and effective antagonism of both activins than did inhibin B, and activin A was less subject to antagonism by either inhibin than was activin B. In contrast to the major antagonism of activin by both inhibins, only inhibin A antagonized the actions of BMP-2, BMP-6, and BMP-7, whereas inhibin B was ineffective against all tested BMP isoforms except BMP-7 at high concentrations. These results provide limited support for the anti-BMP model of inhibin action and reveal that, relative to inhibin A, inhibin B essentially behaves as a selective activin antagonist in AC cells. In conclusion, inhibins A and B differentially antagonize the actions of activins and BMPs to control adrenocortical C₁₉ steroid production.

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