Sphingosine I Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells
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Sphingosine 1 Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells
Reproductive Sciences 1-8 ยช The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1933719119828112 journals.sagepub.com/home/rsx
Osamu Yoshino, MD, PhD1,4, Kaori Yamada-Nomoto1, Kuniyuki Kano, PhD2, Yosuke Ono, MD, PhD1, Mutsumi Kobayashi, MD1, Masami Ito, MD1, Satoshi Yoneda, MD, PhD1, Akitoshi Nakashima, MD, PhD1, Tomoko Shima, MD, PhD1, Takashi Onda, MD, PhD4, Yutaka Osuga, MD, PhD3, Junken Aoki, PhD2, and Shigeru Saito, MD, PhD1
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-1b (IL-1b) or transforming growth factor-b exhibited 2.7-fold and 11.5fold 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 dosedependently. 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. Keywords endometriosis, IL-6, inflammation, S1P, SphK1
Introduction Endometriosis is a gynecological condition in women of reproductive age, of which the primary symptoms are infertility and pelvic pain.1-4 Endometriosis is defined as the presence of viable endometrial glands and/or stroma outside of the uterine cavity. Multiple lines of evidence suggest that inflammation plays a pivotal role in the pathogenesis and development of the disease.4-8 We also have shown that aberrant secretion of inflammatory substances such as prostaglandin, interleukin (IL)-1b, IL-6, IL-8 and monocyte chemoattractant protein 1, play important roles in pathophysiology of endometriosis.9,10 Although reduction of inflammation seems to be an important strategy for controlling endometriosis, 5-8 antiinflammatory therapy has not been established. Therefore, it is essential to explore inflammatory substances which have strong impact on the disease. In pursuit of as-yet-unidentified pro-inflammatory
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