Interferon-γ and Activin A Promote Insulin-Like Growth Factor-Binding Protein-2 and -4 Accumulation by Human Luteinizing Granulosa Cells, and Interferon-γ Promotes Their Apoptosis1

Abstract

Insulin-like growth factor (IGF)-binding proteins (IGFBPs) antagonize IGF and gonadotropin actions on granulosa cells. Human atretic follicles express IGFBP-2 in granulosa cells more strongly and contain higher levels of IGFBP-2 and IGFBP-4 than healthy follicles. We studied the effects of interferon-γ (IFNγ) and activin A, which decrease progesterone accumulation, on granulosa cell IGFBP production and apoptosis. Conditioned media from luteinizing granulosa cells cultured with IFNγ or activin A and/or LH were subjected to ligand blotting; northern blots of total ribonucleic acid (RNA) from these cells were probed for IGFBP-2 and -4. Apoptosis was measured by in situ DNA end labeling. LH decreased medium IGFBP-2 to 21% of the control value. Although IFNγ did not alter basal medium IGFBP-2, in the presence of LH it increased IGFBP-2 3.4-fold, with parallel changes in messenger RNA levels. Activin A also tended to increase medium IGFBP-2 in LH-treated cultures. In conditioned medium, IGFBP-4 was consistently decreased by LH, whereas both IFNγ and activin A increased IGFBP-4 and decreased IGFBP-4 protease activity. Both LH and IFNγ modestly stimulated IGFBP-4 messenger RNA levels. Follistatin antagonized the action of activin A, but not that of IFNγ. IFNγ, but not activin A, increased granulosa cell apoptosis. In conclusion, IFNγ produced by activated lymphocytes may decrease endogenous IGF activity through stimulation of IGFBPs and may promote apoptosis of granulosa-lutein cells in vivo and, thus, luteal regression. Activin A similarly promotes IGFBP accumulation, but it does not promote apoptosis. (J Clin Endocrinol Metab 83: 179–186, 1998)