Inhibin antagonizes activin and BMP actions by sequestering their type II receptors in high affinity complexes with betaglycan, a co-receptor that inhibin shares with TGF-. To clarify the nature and extent of interactions between inhibin and TGF-, we therefore examined i) the mutual competition between these ligands for binding, ii) the regulation of endogenous betaglycan expression by inhibin and TGF- isoforms, and iii) the consequences of such betaglycan regulation for subsequent inhibin binding in mouse Leydig (TM3), Sertoli (TM4), adrenocortical cancer (AC) and gonadotroph (LT2) cell lines, chosen to model cellular targets for local and endocrine actions of inhibin.

Recognized inhibin, activin and TGF- binding proteins and TGF-/activin signalling components were expressed by all four cell types, but AC and LT2 cells notably lacked the type II receptor for TGF-, TRII. Overnight treatment of TM3 and TM4 cells with TGF-1 suppressed the levels of betaglycan mRNA by 73 and 46% of control, and subsequent [¹²⁵I]inhibin A binding by 64 and 41% of control (IC50 of 54 and 92 pM), respectively. TGF-2 acted similarly. TGF- pre-treatments commensurately decreased the [¹²⁵I]inhibin A affinity labelling of betaglycan on TM3 and TM4 cells. TGF- isoforms as direct competitors blocked up to 60% of specific inhibin A binding sites on TM3 and TM4 cells, but with 9- to 17-fold lower potency than when acting indirectly via regulation of betaglycan. Only the competitive action of TGF- was observed with TRII-deficient AC and LT2 cells. Neither inhibin A nor inhibin B regulated betaglycan mRNA or competed for binding of [¹²⁵I]TGF-1 or -2. Thus, inhibin binding to its target cell types is controlled by TGF- through dual mechanisms of antagonism, the operation of which vary with cell context and display different sensitivities to TGF-. In contrast, TGF- binding is relatively insensitive to the presence of either inhibin A or inhibin B.