Transforming growth factor-alpha stimulates insulin-like growth factor binding protein-4 (IGFBP-4) expression and blocks follicle-stimulating hormone regulation of IGFBP-4 production in rat granulosa cells

The ability of TGF-alpha: to regulate insulin-like growth factor binding protein-4 (IGFBP-4), was investigated. Primary cultures of rat granulosa cells (GC) were grown in serum-free medium with rat (r) TGF-alpha and/or rFSH, and secreted IGFBP-4 protein and its steady state mRNA levels were measured by Western immunoblotting and Northern blotting, respectively. Control (untreated) cells secreted IGFBP-4 spontaneously, and the levels were increased by rTGF-alpha in a dose-and time-dependent manner. rTGF-alpha abolished FSH-induced IGFBP-4 protease activity and suppressed FSH-dependent effects on IGFBP-4 production. IGFBP-4 mRNA levels were decreased and increased by FSH and TGF-alpha, respectively, and TGF-alpha blocked the FSH effects. These results demonstrate that TGF-alpha is a potent stimulator of IGFBP-4 expression in rat GC and can overcome the regulatory effects of FSH on IGFBP-4 production. The consequence of these TGF-alpha effects is a marked, sustained increase in the levels of IGFBP-4 in the microenvironment. (C) 1997 Elsevier Science Ireland Ltd.