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Phospholipase D1 as a Key Enzyme for Decidualization in Human Endometrial Stromal Cells¹

Departments of Biochemistry and Molecular Biology,³ Obstetrics and Gynecology,⁴ and Medicine,⁵ College of Medicine, Hanyang University, Seoul 133-791, Korea The Research Center for Bio-Medical Resources,⁶ Paichai University, Taejon 302-735, Korea

ABSTRACT

Using primary cell cultures of human endometrial stromal cells (ES cells), we investigated the role of phospholipase D (PLD) in 8-Br-cAMP-induced decidualization, which involves morphological and biological differentiation processes. When treated with 0.5 mM 8-Br-cAMP for 12 days, ES cells were transformed into a decidualized morphology and produced significant amounts of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP1). Simultaneously, the activity and expression levels of PLD1 increased. In addition, removal of 8-Br-cAMP from decidualized ES cells restored the undifferentiated state, and this was accompanied by decreases in PLD1 promoter activity and PLD1 expression. Overexpression of dominant negative (DN)-PLD1 inhibited the morphological changes induced by 0.5 mM 8-Br-cAMP, whereas PLD1 overexpression induced morphological changes in the absence of 0.5 mM 8-Br-cAMP treatment. Moreover, knockdown of PLD1 by siRNA and blockage of PLD by treatment with 0.3% 1-butanol decreased PRL/IGFBP1 mRNA expression, whereas PLD1 overexpression increased PRL/IGFBP1 mRNA expression. Treatment of ES cells with phosphatidic acid (PA) for 3 days induced PRL mRNA expression and morphological changes, which implies that PA is an end-product of PLD activation-induced decidualization. In addition, pretreatment of ES cells with mepacrine decreased PRL/IGFBP1 expression and inhibited morphological change, whereas pretreatment with propranolol caused no changes, as compared to cAMP-treated cells, which suggests that PA induces decidualization through phospholipase A2 (PLA2G1B). Taken together, these results suggest that PLD1 regulates 8-Br-cAMP-induced decidualization through PLA2G1B, and that PLD1 upregulation is essential for the decidualization of ES cells.

8-Br-cAMP, developmental biology, decidualization, human endometrial stromal cell, phospholipase

¹Supported by the Korea Research Foundation (015-E00070, 2004) and partially supported by KOSEF and MOST through the Research Center for Biomedicinal Resources (Bio-Med RRC), Paichai University.

Correspondence: ²Joong-Soo Han, Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, 17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Korea. FAX: 822 2294 6270; e-mail: jshan{at}hanyang.ac.kr

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