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Pregnenolone Sulfate Regulates Prolactin Production in the Rat Pituitary

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Pregnenolone Sulfate Regulates Prolactin Production in the Rat Pituitary 230 3 E-J KANG and others The regulation of prolactin by PS 230:3 339–346 Research Pregnenolone sulfate regulates prolactin production in the rat pituitary Eun-Jin Kang1, So-Hye Hong1, Jae-Eon Lee1, Seung Chul Kim2, Hoe-Saeng Yang3, Pyong in Yi4, Sang-Myeong Lee5 and Beum-Soo An1 1Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Milyang, Republic of Korea 2Department of Obstetrics and Gynecology, Biomedical Research Institute, Pusan National University School of Medicine, Milyang, Republic of Korea Correspondence 3Department of Obstetrics and Gynecology, Medical College, Dongguk University, Seoul, Republic of Korea should be addressed 4Department of Bioenvironmental Energy, College of Natural Resources and Life Science, Pusan National University, to B-S An Milyang, Republic of Korea Email 5College of Environmental and Bioresource Sciences, Chonbuk National University, Jeonju, Republic of Korea [email protected] Abstract Pregnenolone sulfate (PS) is a neuroactive steroid hormone produced in the brain. Key Words In this study, the effects of PS on synthesis and secretion of rat pituitary prolactin (PRL) f pregnenolone sulfate Endocrinology were examined. To accomplish this, GH3 rat pituitary adenoma cells were treated with f neurosteroid of PS, which showed significantly increased mRNA and protein levels of PRL compared with f pituitary prolactin the control. The mechanism of action responsible for the effects of PS on PRL synthesis Journal and secretion was investigated by pretreating cells with inhibitors of traditional PRL- or the PS-related signaling pathway. PS-stimulated PRL transcription was significantly reduced by inhibitors of PKA, PKC and MAPK, but unchanged by GABAAR and NMDAR inhibitors. Western blotting analysis revealed that the total ERK1/2 level was upregulated in a time-dependent manner following PS treatment. An approximate 10% increase in GH3 cell proliferation was also observed in response to PS relative to the control. In the animal study, levels of PRL in the pituitary and in serum were elevated by PS. PS-stimulated PRL synthesis was also found to be associated with decreased expression of PRL target genes such as GNRH1, FSHB and LHB. These findings show that PS upregulates PRL synthesis and secretion in vivo and in vitro via MAPK signaling, suggesting that it has the potential for use as a therapeutic hormone to treat PRL- related disorders such as hypoprolactinemia and low milk supply. Journal of Endocrinology (2016) 230, 339–346 Introduction Prolactin (PRL) is a polypeptide hormone synthesized synthesis of milk (lactogenesis) and maintenance of and secreted from specialized cells of the anterior milk secretion (galactopoiesis) (Freeman et al. 2000). In pituitary gland, which is known for its multiple effects addition, the range of PRL functions has greatly increased on the female mammary gland, including regulation of in females and males. An early review revealed that PRL growth and development of the gland (mammogenesis), had 85 functions (Cowie 1973), which has subsequently http://joe.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0088 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:22:16AM via free access 10.1530/JOE-16-0088 Research E-J KANG and others The regulation of prolactin by PS 230:3 340 been updated to over 300, including immune functions, GH3 cells stimulates phosphorylation of PIT-1 is reproduction, osmoregulation and behavior (Bole-Feysot consistent with a role of PIT-1 in regulation of PRL et al. 1998). transcription (Kapiloff et al. 1991). PRL-inhibiting factors (PIFs) and PRL-releasing Pregnenolone sulfate (PS) is an endogenous factors (PRFs) supplied by neurosecretory cells control neuroactive steroid metabolized from pregnenolone synthesis and secretion of PRL from the pituitary (Arey (P5), which is a precursor of endogenous steroid et al. 1989, Lamberts & Macleod 1990). The PIF includes hormones such as progesterone (P4) and estrogen (E2). dopamine (DA), somatostatin and gamma-aminobutyric Neuroactive steroids synthesized directly in the brain acid (GABA), whereas PRF includes thyrotropin-releasing are independent from peripheral sources and rapidly hormone (TRH), neurotensin and oxytocin. Internal alter neuronal excitability by binding to their receptors milieu such as suckling, stress and increased levels of (Baulieu 1998). PS is endogenously present in the brain ovarian steroids modulate PRF and PIF activities, which and synthesized by glial cells, which has been shown to transduce PRL-regulating signals (Meites et al. 1963, Neill modulate neurotransmission in a variety of systems via 1970, Terkel et al. 1972). both presynaptic and postsynaptic mechanisms (Bowlby DA is the predominant hypothalamic factor 1993). PS is also known to have cognitive and memory- involved in regulation of PRL synthesis and secretion. enhancing, antidepressant, anxiogenic and proconvulsant In addition, factors influencing the dopaminergic tone effects (Reddy 2010). in lactotrophs have been investigated to illuminate Although PS is defined as a neurosteroid hormone, the complex connection between PRL and DA. DA its mechanisms and functions have not been well directly influences lactotrophs by binding to the established. Neuroactive steroids including PS could affect D2 receptor (D2R) subclass expressed on their cell the pituitary cells (Le Foll 1997). Therefore, this study membranes (Lefkowitz & Labrie 1978). Other pituitary- examined the effects of PS on synthesis and secretion of derived factors also regulate PRL secretion, including PRL and also the PRL target genes in the rat pituitary. transforming growth factor alpha (TGF-α), transforming Endocrinology growth factor beta (TGF-β), interleukins and galanin of (Sarkar et al. 1998). In addition, the secretion and Materials and methods synthesis of PRL are modulated by calcium (Ca2+) Cell culture and treatments concentration. PRL secretion is sensitive to changes in Journal extracellular Ca2+ concentration in normal rat pituitary GH3 rat pituitary epithelial-like tumor cells were cells in vitro. TRH stimulates PRL release via elevated cultured in DMEM (Gibco) supplemented with 10% fetal intracellular free Ca2+ (Gershengorn 1986). Chelation bovine serum (FBS; Welgene, Seoul, Korea), 100 U/mL of extracellular Ca2+ has been shown to reduce PRL penicillin, and 100 μg/mL streptomycin (Welgene) secretion and synthesis in the GH3 pituitary cells. at 37°C in a humidified atmosphere of 5% CO2 and TRH-stimulated PRL secretion is also suppressed by 95% air. Cells were seeded in DMEM culture medium. reduction of Ca2+ and verapamil (Ca2+ channel blocker) After 24 h the medium was replaced by phenol red-free (Gershengorn & Thaw 1985). DMEM (Sigma-Aldrich) supplemented with 10% Transcription of PRL likely involves activation of charcoal/dextran-treated FBS (Hyclone, Logan, UT, USA), protein kinases, which leads to phosphorylation of 100 U/mL penicillin and 100 μg/mL streptomycin for specific regulators such as PIF and PRF. Activation of 24 h before treatment. All the chemicals for treatment cAMP-dependent protein kinase (PKA), protein kinase were dissolved in ethanol, diluted with experimental C (PKC), Ca2+/calmodulin-dependent protein kinase medium, and added to the cell culture medium. The type II, or the mitogen-activated protein kinase (MAPK) tumor cells were treated with E2 (100 nM), P4 (10 μM), cascade has been shown to be sufficient to stimulate P5 (10 μM), PS (100 μM) or ethanol (EtOH) to obtain transcription of the PRL gene. The PRL promoter contains the vehicle control. The cells were also pretreated with multiple binding sites for tissue-specific transcription muscimol (Mus; 10 μM), 3-[(R)-2-carboxypiperazin- factor including pituitary-specific positive transcription 4-yl]-prop-2-enyl-1-phosphonic acid (CPP; 10 μM), factor 1(PIT-1), and PIT-1 binding sites may contribute H89 (10 μM), staurosporine (Sta; 1 μM) or PD98059 to hormonally regulation and basal transcription of PRL. (PD; 10 μM) 1 h before PS treatment to block PRL or The finding that cAMP or phorbol ester treatment of PS signaling. http://joe.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0088 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:22:16AM via free access Research E-J KANG and others The regulation of prolactin by PS 230:3 341 Experimental animals and treatments specific primers. Primer sequences for PRL, D2R, PIT-1, V-Ets Avian Erythroblastosis Virus E 6 Oncogene Immature female Sprague–Dawley (n = 30) rats were 2 Homolog 1 (ETS-1), gonadotropin-releasing hormone acquired from Samtako (Osan, Republic of Korea). (GNRH1), gonadotropin-α, follicle-stimulating hormone The rats were housed at the Pusan National University beta (FSHB), and luteinizing hormone beta (LHB) are Laboratory Animal Resources Center, which is accredited shown in Table 1. Real-time PCR was conducted by by the Korea FDA, according to the National Institutes subjecting the samples to 40 cycles of denaturation at of Health guidelines. The rats were housed in cages 95°C for 15 s, followed by annealing and extension at under a 12 h light:12 h darkness cycle and a constant 70°C for 60 s. Fluorescence intensity was measured temperature of 23 ± 1°C. The Ethics Committee of at the end of the extension phase of each cycle. The Pusan National University (Busan, Republic of Korea) threshold value for fluorescence intensity of all samples approved all experimental animal procedures (approval was set manually. The reaction cycle at which the PCR number; PNU-2014-0665). Rats were treated daily with PS products exceeded this fluorescence intensity threshold (10 mg/kg/day), E2 (40 μg/kg/day), P4 (1 mg/kg/day), during the exponential phase of PCR amplification was P5 (10 mg/kg/day) or corn oil (vehicle control) via considered to be the threshold cycle (CT). Expression subcutaneous injection (SC) from postnatal days (PNDs) of the target gene was quantified relative to that of 17 to 19.
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