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Estrogens Up-Regulate the Fas/FasL Apoptotic Pathway in Lactotropes

Centro de Investigaciones en Reproducción (G.J., M.C., V.Z., S.Z., L.F., D.P., A.S.), Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires (C1121ABG), Argentina; and Gene Therapeutics Research Institute (M.G.C.), Cedars Sinai Medical Center and David Geffen School of Medicine, UCLA, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Adriana Seilicovich, Centro de Investigaciones en Reproducción, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 10, Buenos Aires (C1121ABG), Argentina. E-mail: adyseili{at}fmed.uba.aradyseili@fmed.uba.ar.

The Fas/FasL system provides the major apoptotic mechanism for many cell types, participating in cell turnover in hormone-dependent tissues. In the present study, we localized both Fas and FasL in anterior pituitary cells, mainly in lactotropes and somatotropes. The percentage of anterior pituitary cells showing immunoreactivity for Fas or FasL was higher in cells from rats killed in proestrus than in diestrus. Also, the proportion of pituitary cells from ovariectomized (OVX) rats expressing Fas or FasL increased in the presence of 17ß-estradiol (10^–9 M). This steroid increased the percentage of lactotropes with immunoreactivity for Fas or FasL and the percentage of somatotropes expressing Fas. Activation of Fas by an agonist anti-Fas antibody (Mab-Fas) decreased the vi-ability—3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT assay)—of anterior pituitary cells from OVX rats cultured in the presence of 17ß-estradiol. Also, membrane-bound FasL decreased cell viability—[3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay (MTS assay)—only when anterior pituitary cells from OVX rats were incubated with 17ß-estradiol. Moreover, FasL increased the percentage of hypodiploid anterior pituitary cells (flow cytometry). Mab-Fas increased the percentage of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive pituitary cells and lactotropes from OVX rats only when cells were incubated in the presence of 17ß-estradiol. Also, Mab-Fas triggered apoptosis of anterior pituitary cells from rats killed at proestrus but not at diestrus. Our results show that 17ß-estradiol up-regulates the expression of the Fas/FasL system in anterior pituitary cells and increases Fas-induced apoptosis in lactotropes, suggesting that Fas-induced apoptosis could be involved in the pituitary cell renewal during the estrous cycle.

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