title: Induction of Fas-Mediated Apoptosis by Interferon-γ is Dependent on Granulosa Cell Differentiation and Follicular Maturation in the Rat Ovary.
abstract: Fas ligand (FasL) and its receptor Fas have been implicated in granulosa cell apoptosis during follicular atresia. Although interferon-gamma (IFN-γ) is believed to be involved in the regulation Fas expression in differentiated granulosa or granulosa-luteal cells, the expression of this cytokine and its role in the regulation of the granulosa cell Fas/FasL system and apoptosis during follicular maturation have not been thoroughly investigated. In the present study, we have examined the presence of IFN-γ in ovarian follicles at different stage of development by immunohistochemistry and related their relative intensities with follicular expression of Fas and FasL, and with differences in granulosa cell sensitivity to Fas activation by exogenous agonistic Anti-Fas monoclonal antibody (Fas mAb). Although IFN-γ immunostaining was detectable in oocyte and granulosa cells in antral follicles, most intense immunoreactivity for the cytokine was observed in these cells of preantral follicles. Intense immunoreactivity for IFN-γ was most evident in granulosa cells of atretic early antral follicles where increased Fas and FasL expression and apoptosis were also observed. Whereas low concentrations of IFN-γ (10-100 U/mL) significantly increased Fas expression in undifferentiated granulosa cells (from preantral or very early antral follicles)in vitro, very higher concentrations (≥ 1,000 U/mL) were required to up-regulate of Fas in differentiated cells isolated from eCG-primed (antral) follicles. Addition of agonistic Fas mAb to cultures of granulosa cells at the two stages of differentiation and pretreated with IFN-γ (100 U/mL) elicited morphological and biochemical apoptotic features which were more prominent in cells not previously exposed to the gonadotropinin vivo. These findings suggested that IFN-γ is an important physiologic intra-ovarian regulator of follicular atresia and plays a pivotal role in regulation of expression of Fas receptor and subsequent apoptotic response in undifferentiated (or poorly differentiated) granulosa cells at an early (penultimate) stage of follicular development.
authors.affiliation: Department of Pharmacology, College of Medicine, Dong-A University, Busan 602-714, Korea.
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Department of Life Science, College of Natural Sciences, Hanyang University, Seoul 133-791, Korea.
authors.forename: Yong-Dal
authors.initials: YD
authors.lastname: Yoon
authors.affiliation: Department of Obstetrics and Gynecology and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1Y 4E9.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Tsang
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714, Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Kim
keywords: Apoptosis; Fas; Granulosa cells; Interferon-γ; Ovary