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Sphingosine I Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells

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Abstract

Objects: There is growing evidence that sphingosine 1-phosphate (S1P) is involved in inflammatory diseases. As endometriosis is known as an inflammatory disease, we investigated the role of S1P system in the development of endometriosis. Methods: The expression of sphingosine kinase (SphK) 1 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors were obtained to measure S1P concentrations. Endometriotic stromal cells (ESC) derived from endometrioma were used for in vitro experiments. Results: Sphingosine kinase 1 was detected in epithelium and stromal cells of endometriotic lesions. The mean S1P concentration in the cystic fluid of endometriomas was higher than that in nonendometriomas significantly (98.2 nM vs less than 1.5 nM, P <.01). Interleukin-1β (IL-1β) or transforming growth factor-β exhibited 2.7-fold and 11.5-fold increase in SphK1 messenger RNA (mRNA) expression in ESC, respectively (P <.01). Higher dose of S1P (125nM) increased the cell number of ESC by 20%, and low dose of S1P (1.25 nM and 12.5 nM) induced IL-6 mRNA production and IL-6 secretion by ESC dose-dependently. JTE013, an antagonist for S1PR2, partially suppressed IL-6 induction by S1P (P <.05). JTE013 and VPC23019, an antagonist for S1PR1 and S1PR3, suppressed the ESC proliferation induced by S1P. Conclusion: The present study for the first time proved that the SphK-S1P-S1PR axis play a role of accelerating inflammation and growth of endometriotic cells.

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Acknowledgments

Authors thank Dr Heather M. Martinez for her helpful discussion and critical reading of the manuscript and Ms Maiko Mizuguchi for her excellent technical assistance.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan

    Osamu Yoshino, Kaori Yamada-Nomoto, Yosuke Ono, Mutsumi Kobayashi, Masami Ito, Satoshi Yoneda, Akitoshi Nakashima, Tomoko Shima & Shigeru Saito

  2. Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan

    Kuniyuki Kano & Junken Aoki

  3. Department of Obstetrics and Gynecology, University of Tokyo, Tokyo, Japan

    Yutaka Osuga

  4. Department of Obstetrics and Gynecology, Kitasato University, School of Medicine, Kanagawa, Japan

    Osamu Yoshino & Takashi Onda

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  1. Osamu Yoshino
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  2. Kaori Yamada-Nomoto
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Correspondence to Shigeru Saito.

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Yoshino, O., Yamada-Nomoto, K., Kano, K. et al. Sphingosine I Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells. Reprod. Sci. 26, 1460–1467 (2019). https://doi.org/10.1177/1933719119828112

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  • DOI: https://doi.org/10.1177/1933719119828112

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