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IL-33 Exacerbates Endometriotic Lesions via Polarizing Peritoneal Macrophages to M2 Subtype

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Abstract

In endometriosis, M2 macrophages (MΦ) are dominant and promote the development of endometriosis lesions. However, the factor(s) which induces M2 MΦ are unknown. In the present study, we focused on interleukin (IL)-33, known as an alarmin and investigated its expression and its role in endometriosis, especially from the point of the relevance with MΦ. The expression of IL-33 in endometriosis lesions was examined by immunohistochemistry. The cystic fluid of ovarian cysts/tumors was obtained and used to measure IL-33 concentration. Endometriotic stromal cells (ESC) and MΦ derived from patients were used for in vitro experiments. IL-33 was detected in the epithelium and stromal cells of endometriotic lesions. The mean IL-33 concentration in the cystic fluid of endometriomas was significantly higher than that in non-endometriomas (2.2 ng/ml vs. 0.02 ng/ml, P < 0.01). IL-1β induced IL-33 mRNA expression in ESC via p38 MAPK activation. With IL-33 stimulation, peritoneal MΦ polarized to M2 MΦ and produced IL-1β mRNA with a 2.2-fold increase, which was negated with soluble ST2, a decoy receptor of IL-33. IL-33, derived from endometriotic lesions, stimulated MΦ to produce IL-1β, which results in increasing IL-33 production in ESC. This cycle may continue to exacerbate the endometriotic lesions.

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Acknowledgments

We thank Dr. Heather M. Martinez for her helpful discussion and critical reading of the manuscript.

Funding

This work was supported by Health and Labor Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology.

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Authors and Affiliations

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

    Yosuke Ono, Masami Ito, Mutsumi Kobayashi & Akitoshi Nakashima

  2. Department of Obstetrics and Gynecology, Teine Keijinkai Hospital, Sapporo, Japan

    Yosuke Ono & Shinichiro Wada

  3. Department of Obstetrics and Gynecology, Kitasato University School Medicine, Sagamihara, Japan

    Osamu Yoshino, Takehiro Hiraoka, Erina Sato, Takashi Onda & Nobuya Unno

  4. Department of Obstetrics and Gynecology, University of Tokyo, Bunkyo, Tokyo, Japan

    Ikumi Akiyama & Yutaka Osuga

Authors
  1. Yosuke Ono
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  2. Osamu Yoshino
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  3. Takehiro Hiraoka
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  4. Ikumi Akiyama
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  5. Erina Sato
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  6. Masami Ito
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  7. Mutsumi Kobayashi
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  8. Akitoshi Nakashima
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  9. Shinichiro Wada
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  10. Takashi Onda
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  11. Nobuya Unno
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  12. Yutaka Osuga
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Correspondence to Osamu Yoshino.

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The authors declare that they have no conflict of interest.

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Ono, Y., Yoshino, O., Hiraoka, T. et al. IL-33 Exacerbates Endometriotic Lesions via Polarizing Peritoneal Macrophages to M2 Subtype. Reprod. Sci. 27, 869–876 (2020). https://doi.org/10.1007/s43032-019-00090-9

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  • DOI: https://doi.org/10.1007/s43032-019-00090-9

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