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IFN-τ Attenuates LPS-Induced Endometritis by Restraining HMGB1/NF-κB Activation in bEECs

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Abstract

Endometritis is a common inflammatory disease in uterine tissues that leads to animal infertility. Among the causes, Escherichia coli infection is one of the main reasons. Interferon-tau (IFN-τ) is the initial pregnancy signal for ruminant embryos and can induce immune tolerance in humans and other species. However, there are scarce reports on whether IFN-τ has a regulatory effect on endometrial inflammatory damage through HMGB1-NF-κB signalling. The purpose of this study was to investigate the regulatory mechanism of IFN-τ in HMGB1-NF-κB signalling in LPS-induced endometritis. ELISA and qPCR were used to detect the expression of LPS-induced pro-inflammatory cytokines in bovine endometrial epithelial cells (bEECs or BEND) under IFN-τ intervention, and the levels of HMGB1, p-IKK and p-p65 were detected by Western blotting. The nuclear translocation of NF-κB p65 was determined through immunofluorescence. In addition, bEECs were transfected with si-HMGB1 to elucidate the key role of HMGB1 and IFN-τ in the endometrial inflammatory cascade. The results indicated that IFN-τ inhibits the expression of related pro-inflammatory cytokines in an inflammatory injury model of bovine endometrial epithelial cells induced by LPS. Furthermore, experiments have proven that IFN-τ has protective effects on E. coli endotoxin-induced endometritis in mice in vivo. IFN-τ inhibited the HMGB1-NF-κB axis and significantly reduced the secretion of pro-inflammatory cytokines, the expression of HMGB1 protein and the levels of IKK and NF-κB p65 phosphorylation. In summary, our results showed that IFN-τ resists E. coli endotoxin-induced endometritis by attenuating HMGB1/NF-κB signalling.

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Data Availability

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Swangchan-Uthai, T., C.R.M. Lavender, Z. Cheng, A.A. Fouladi-Nashta, and D.C. Wathes. 2012. Time course of defense mechanisms in bovine endometrium in response to lipopolysaccharide1. Biology of Reproduction 87: 135.

    Article  Google Scholar 

  2. Roberto Romero MDJE. can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization. 2004; 4.

  3. Le Blanc, S.J. 2012. Interactions of metabolism, inflammation, and reproductive tract health in the postpartum period in dairy cattle. Reproduction in Domestic Animals 47: 18–30.

    Google Scholar 

  4. Haimerl, P., and W. Heuwieser. 2014. Invited review: antibiotic treatment of metritis in dairy cows: a systematic approach. Journal of Dairy Science 97: 6649–6661.

    Article  CAS  Google Scholar 

  5. Ledgard, A.M., R.S.F. Lee, and A.J. Peterson. 2009. Bovine endometrial legumain and TIMP-2 regulation in response to presence of a conceptus. Molecular Reproduction and Development 76: 65–74.

    Article  CAS  Google Scholar 

  6. Sheldon, I.M., S.B. Price, J. Cronin, R.O. Gilbert, and J.E. Gadsby. 2009. Mechanisms of infertility associated with clinical and subclinical endometritis in high producing dairy cattle. Reproduction in Domestic Animals 44: 1–9.

    Article  Google Scholar 

  7. Zhao, J., Y. Zheng, K. Liu, J. Chen, N. Lai, F. Fei, et al. 2019. HMGB1 Is a therapeutic target and biomarker in diazepam-refractory status epilepticus with wide time window. Neurotherapeutics.

  8. Zhang C, Wang L, Li T, Mao W, Liu B, Cao J. EP2/4 receptors promotes the synthesis of PGE2 increasing tissue damage in bovine endometrial explants induced by Escherichia coli. Journal of Pharmacology and Experimental Therapeutics 2019:jpet.119.262444.

  9. Xu, Y., N. Li, R. Xiang, and P. Sun. 2014. Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends in Biochemical Sciences 39: 268–276.

    Article  CAS  Google Scholar 

  10. Tong, L., Y. Yuan, and S. Wu. 2015. Therapeutic microRNAs targeting the NF-kappa B signaling circuits of cancers. Advanced Drug Delivery Reviews 81: 1–15.

    Article  CAS  Google Scholar 

  11. Hoste E, Maueröder C, van Hove L, Catrysse L, Vikkula H, Sze M, et al. Epithelial HMGB1 delays skin wound healing and drives tumor initiation by priming neutrophils for NET formation. Cell Reports 2019; 29:2689-2701.e4.

  12. Shang, L. 2019. HMGB1 was negatively regulated by HSF1 and mediated the TLR4/MyD88/NF-κB signal pathway in asthma. Life Sciences.

  13. Godkin, J.D., and FWBJ. 1982. Purification and properties of a major, low molecular weight protein released by the trophoblast of sheep blastocysts at day 13-21. J. Reptrod. Fert 65: 141–150.

    Article  CAS  Google Scholar 

  14. Padilla-Quirarte, H.O., C. Trejo-Moreno, G. Fierros-Zarate, J.C. Castañeda, M. Palma-Irizarry, E. Hernández-Márquez, A.I. Burguete-Garcia, O. Peralta-Zaragoza, V. Madrid-Marina, K. Torres-Poveda, and V.H. Bermúdez-Morales. 2016. Interferon-tau has antiproliferative effects, represses the expression of E6 and E7 oncogenes, induces apoptosis in cell lines transformed with HPV16 and inhibits tumor growth in vivo. Journal of Cancer 7: 2231–2240.

    Article  CAS  Google Scholar 

  15. Takino, T., T. Okamura, T. Ando, and K. Hagiwara. 2016. Change in the responsiveness of interferon-stimulated genes during early pregnancy in cows with Borna virus-1 infection. BMC Veterinary Research 12: 253.

    Article  Google Scholar 

  16. Jiang, K., X. Chen, G. Zhao, H. Wu, J. Mi, C. Qiu, X. Peng, and G. Deng. 2017. IFN-τ plays an anti-inflammatory role in Staphylococcus aureus-induced endometritis in mice through the suppression of NF-κB pathway and MMP9 expression. Journal of Interferon & Cytokine Research 37: 81–89.

    Article  CAS  Google Scholar 

  17. Hara, K., K. Shirasuna, F. Usui, T. Karasawa, Y. Mizushina, H. Kimura, A. Kawashima, A. Ohkuchi, S. Matsuyama, K. Kimura, and M. Takahashi. 2014. Interferon-tau attenuates uptake of nanoparticles and secretion of interleukin-1β in macrophages. PLoS ONE 9: e113974.

    Article  Google Scholar 

  18. Wu, H., K. Jiang, S. Guo, J. Yang, G. Zhao, C. Qiu, and G. Deng. 2018. IFN-τ Mediated control of bovine major histocompatibility complex class I expression and function via the regulation of bta-miR-148b/152 in bovine endometrial epithelial cells. Frontiers in Immunology 9.

  19. Zhang, S., B. Liu, L. Gao, W. Mao, C. Fu, D. Duritahala, et al. 2017. Prostaglandin F2 alpha-PTGFR signalling activation, growth factor expression and cell proliferation in bovine endometrial explants. Reprod Fertil Dev 29: 2195–2205.

    Article  CAS  Google Scholar 

  20. Sheldon, I.M., J. Cronin, L. Goetze, G. Donofrio, and H. Schuberth. 2009. Defining postpartum uterine disease and the mechanisms of infection and immunity in the female reproductive tract in cattle1. Biology of Reproduction 81: 1025–1032.

    Article  CAS  Google Scholar 

  21. Ahmadi, M.R., M. Makki, A. Mirzaei, and H.R. Gheisari. 2019. Effects of hypertonic dextrose and paraffin solution as non-antibiotic treatments of clinical endometritis on reproductive performance of high producing dairy cows. Reproduction in Domestic Animals 54: 762–771.

    Article  CAS  Google Scholar 

  22. Tanikawa, N., K. Seno, R. Kawahara-Miki, K. Kimura, S. Matsuyama, H. Iwata, T. Kuwayama, and K. Shirasuna. 2017. Interferon tau regulates cytokine production and cellular function in human trophoblast cell line. Journal of Interferon & Cytokine Research 37: 456–466.

    Article  CAS  Google Scholar 

  23. Palma-Vera, S.E., and R. Einspanier. 2016. Experimental and bioinformatic analysis of cultured bovine endometrial cells (BEND) responding to interferon tau (IFNT). Reproductive Biology and Endocrinology 14: 22.

    Article  Google Scholar 

  24. Yang, D., T. Jiang, J. Liu, J. Hong, P. Lin, H. Chen, D. Zhou, K. Tang, A. Wang, and Y. Jin. 2018. Interferon-τ regulates prostaglandin release in goat endometrial stromal cells via JAB1-unfolded protein response pathway. Theriogenology 113: 237–246.

    Article  CAS  Google Scholar 

  25. Kagan, J.C. 2017. Lipopolysaccharide detection across the kingdoms of life. Trends in Immunology 38: 696–704.

    Article  CAS  Google Scholar 

  26. Tsan, M., and B. Gao. 2004. Endogenous ligands of toll-like receptors. Journal of Leukocyte Biology 76: 514–519.

    Article  CAS  Google Scholar 

  27. Li, T., W. Mao, B. Liu, R. Gao, S. Zhang, J. Wu, C. Fu, Y. Deng, K. Liu, Y. Shen, and J. Cao. 2019. LPS induced/mediated PGE2 synthesis through activation of the ERK/NF-κB pathway contributes to inflammatory damage triggered by Escherichia coli-infection in bovine endometrial tissue. Veterinary Microbiology 232: 96–104.

    Article  CAS  Google Scholar 

  28. Netea, M.G., F.L. van de Veerdonk, J.W.M. van der Meer, C.A. Dinarello, and L.A.B. Joosten. 2015. Inflammasome-independent regulation of IL-1-family cytokines. Annual Review of Immunology 33: 49–77.

    Article  CAS  Google Scholar 

  29. Bobbo, V.C.D., C.P. Jara, N.F. Mendes, J. Morari, L.A. Velloso, and E.P. Araújo. 2019. Interleukin-6 expression by hypothalamic microglia in multiple inflammatory contexts: A systematic review. BioMed Research International 2019: 1–11.

    Article  Google Scholar 

  30. Kim JH, Hwang SW, Koh J, Chun J, Lee C, Im JP, et al. Inactive rhomboid protein 2 mediates intestinal inflammation by releasing tumor necrosis factor–α. inflammatory bowel diseases 2019.

  31. Shaukat, A., Y. Guo, K. Jiang, G. Zhao, H. Wu, T. Zhang, Y. Yang, S. Guo, C. Yang, A. Zahoor, M. Akhtar, T. Umar, I. Shaukat, S.A. Rajput, M. Hassan, and G. Deng. 2019. Ginsenoside Rb1 ameliorates staphylococcus aureus-induced acute lung injury through attenuating NF-κB and MAPK activation. Microbial Pathogenesis 132: 302–312.

    Article  CAS  Google Scholar 

  32. Jiang, M., C. Xu, Y. Guo, Q. Luo, L. Li, H. Liu, et al. 2018. β-arrestin 2 attenuates lipopolysaccharide-induced liver injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice. World Journal of Gastroenterology 24: 216–225.

    Article  CAS  Google Scholar 

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Acknowledgements

Many thanks to all the members of the veterinary clinical diagnostic laboratory for their meaningful suggestions.

Funding

The research was funded by the National Natural Science Foundation of China. [Nos. 31972744].

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Authors and Affiliations

  1. College of Animal Science, Tarim University, Alar, Xinjiang, 843300, People’s Republic of China

    Junfeng Liu & Xuefeng Guo

  2. Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People’s Republic of China

    Junfeng Liu, Zhimin Wu, Shuai Guo, Tao Zhang, Xiaofei Ma, KangFeng Jiang & Ganzhen Deng

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  1. Junfeng Liu
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  2. Zhimin Wu
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Contributions

J.F.L. and G.Z.D. contributed to the conception and design of the study. J.F.L., S.G., A.Z. and Z.M.W. performed assays and furnished the lab study. T.Z. and X.F.M. performed data collection. Z.M.W. and J.F.L. conducted data analysis. J.F.L., G.Z.D. and X.F.G. drafted the manuscript. J.F.L., K.F.J., X.F.G. and G.Z.D. revised the paper. The authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Xuefeng Guo or Ganzhen Deng.

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Ethics Approval and Consent to Participate

All animal experiments followed international, national and/or institutional guidelines for the care and use of animals. All procedures performed in research involving animals comply with the standards of institutions or practices where ethical research was conducted and had been approved by the Animal Research Ethics Committee of Huazhong Agricultural University (HZAUMO-2015-12).

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Liu, J., Wu, Z., Guo, S. et al. IFN-τ Attenuates LPS-Induced Endometritis by Restraining HMGB1/NF-κB Activation in bEECs. Inflammation 44, 1478–1489 (2021). https://doi.org/10.1007/s10753-021-01433-y

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  • DOI: https://doi.org/10.1007/s10753-021-01433-y

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