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Diminished miR-374c-5p negatively regulates IL (interleukin)-6 in unexplained recurrent spontaneous abortion

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Abstract

Unexplained recurrent spontaneous abortion (URSA) is commonly observed, and seriously affects women’s reproductive health. Excessive interleukin-6 (IL-6) production has been shown to frequently occur and relate to URSA pathogenesis. In this study, the miRNA expression profile in peripheral blood mononuclear cells (PBMCs) from URSA patients and normal pregnant (NP) women was assessed by miRNA microarray and real-time quantitative reverse-transcription polymerase chain reaction (qPCR). MiRNA target prediction tools and luciferase reporter assay were used to detect direct binding between miRNAs and IL6. Functional study of administering anti-IL-6 neutralizing antibody and miR-374c-5p mimics to an URSA animal model was performed to evaluate embryo resorption rates. In the results, compared with NP women, the expression of IL-6 increased markedly in PBMCs and decidual tissues at both mRNA and protein levels, while miR-374c-5p expression decreased significantly. Prediction software and luciferase reporter assay showed that miR-374c-5p binds with IL6 3′UTR via the complementary bases. Transfection of miR-374c-5p mimics into an in vitro HeLa cell line significantly downregulated the expression of IL-6, while transfection of the miR-374c-5p inhibitor induced an opposite result. In the URSA mouse model, miR-374c-5p overexpression reduced the embryo resorption rate significantly, accompanied with decreased expression of IL-6 in the decidua. To sum up, downregulated miR-374c-5p was involved in the pathogenesis of URSA by enhancing IL-6 expression. Modulation of miR-374c-5p expression may be used to regulate IL-6 production for the treatment of URSA.

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Data availability

The data that support the findings of this study are available within the article or on reasonable request from the corresponding author.

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Acknowledgements

We thank Li Han and Guozhen Hei for experimental assistance.

Funding

This work was supported by the Natural Science Foundation of China (81873337), the Project of Transformation in High-tech Achievements (2013ZHZX2A0405), the Natural Science Foundation of Shandong Province (ZR2019MH039), Central Government Guides Local Science and Technology Development Fund Projects of Shandong Province (YDZX20203700001407), Research Leader Studio Project of Jinan Science and Technology Bureau (2020GXRC050), Taishan Scholars (Tsqn 201812125), the Academic Promotion Program of Shandong First Medical University (2019RC005), and the Medical and Health Science and Technology Development Project of Shandong Province (202005021490).

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Author notes

  1. Lin Zhao and Li Han contributed equally to this work.

Authors and Affiliations

  1. Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China

    Chu Chu, Xiaoxiao Fu, Ke Xu & Xia Li

  2. School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, No. 18877 Jingshi Road, Jinan, 250062, Shandong, China

    Lin Zhao, Ran Wei, Zhen Zhang, Xiaoxiao Zhu, Qiang Guo, Xiaoxiao Fu, Ke Xu & Xia Li

  3. Shandong Academy of Chinese Medicine, No. 7 West Yanzishan Road, Jinan, 250014, Shandong, China

    Li Han

  4. Obstetric District of Maternal and Child Health Care of Shandong Province, Jingshi Avenue No. 238, Jinan, 250013, Shandong, China

    Guozhen Hei

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  1. Lin Zhao
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Contributions

Conceptualization: Lin Zhao and Li Han; methodology: Chu Chu, Xiaoxiao Fu, and Ke Xu; formal analysis and investigation: Ran Wei and Xiaoxiao Zhu; writing — original draft preparation: Lin Zhao and Guozhen Hei; writing — review and editing: Zhen Zhang and Xia Li; funding acquisition: Qiang Guo and Xia Li; resources: Xia Li; supervision: Xia Li. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Xia Li.

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Key messages

• URSA has a serious impact on women’s reproductive health.

• IL-6 production has been shown to frequently occur and relate to URSA pathogenesis.

 • Downregulated miR-374c-5p was involved in the pathogenesis of URSA by enhancing IL6 expression.

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Zhao, L., Han, L., Hei, G. et al. Diminished miR-374c-5p negatively regulates IL (interleukin)-6 in unexplained recurrent spontaneous abortion. J Mol Med 100, 1043–1056 (2022). https://doi.org/10.1007/s00109-022-02178-3

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