Inhibins differentially antagonize activin and bone morphogenetic protein action in a mouse adrenocortical cell line.
Inhibin, a member of the TGF-beta 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 17alpha-hydroxylase 17,20-lyase (Cyp17) expression and 17alpha-hydroxylase activity, measured by progesterone 17alpha-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 17alpha-hydroxyprogesterone production (IC(50) 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 17alpha-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 C(19) steroid production.
Farnworth
Paul G
PG
Prince Henry's Institute, P.O. Box 5152, Clayton, Victoria 3168, Australia. paul.farnworth@princehenrys.org
Stanton
Peter G
PG
Wang
Yao
Y
Escalona
Ruth
R
Findlay
Jock K
JK
Ooi
Guck T
GT
D028341:Activins / Q000378:metabolism*; D000302:Adrenal Cortex / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D007265:Inhibins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D051381:Rats; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C525817:Bmp6 protein, mouse; C525818:Bmp6 protein, rat; C525821:Bmp7 protein, rat; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; C422362:inhibin A; C422364:inhibin B; D028341:Activins; D007265:Inhibins; D013254:Steroid 17-alpha-Hydroxylase