Skip to main content

Advertisement

Log in

Programmed cell death protein 1 promotes hepatitis B virus transmission through the regulation of ERK1/2-mediated trophoblasts differentiation

  • General Gynecology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The purpose of our research is to evaluate the mechanism of PD-1 in the promotion of HBV transmission.

Methods

HBV was used to infect two human choriocarcinoma cell line, including JEG-3, as well as BeWo. We used PCR and western blotting to detect PD-1 gene and protein expression levels in cells. Stable knockdown of the PD-1 gene in JEG-3 cells was obtained by lentiviral transfection. Trophoblast cell proliferation was evaluated using CCK8 and flow cytometry. The concentration of HBV antibody in the cell supernatant was measured by ELISA. DNA was then extracted from the cells and the copy number of the HBV virus was detected by PCR. Finally, ERK1/2 expression was detected by western blot.

Results

High PD-1 gene expression in HBV-infected trophoblasts and the knockdown of PD-1 gene can, respectively, improve the proliferation of HBV-infected trophoblasts and reduce viral replication in trophoblasts. In addition, PD-1 and ERK1/2 proteins were co-expressed in HBV-infected trophoblasts and inhibited the activation of ERK1/2 pathway in HBV-infected trophoblasts. ERK1/2 expression significantly increased after PD-1 knockdown. Therefore, PD-1 might be an important protein in trophoblast cells infected with HBV.

Conclusions

PD-1 promoted HBV transmission through regulating ERK1/2-mediated trophoblasts differentiation. Therefore, our research may provide new ideas and methods for preventing mother-to-child transmission of HBV infection during pregnancy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Trépo C, Chan HL, Lok A (2014) Hepatitis B virus infection. Lancet 384:2053–2063

    Article  Google Scholar 

  2. Busch K, Thimme R (2015) Natural history of chronic hepatitis B virus infection. Med Microbiol Immunol 204:5–10

    Article  CAS  Google Scholar 

  3. Ling Z, Liu X, Cheng Y, Jiang X, Jiang H, Wang Y et al (2015) Decreased diversity of the oral microbiota of patients with hepatitis B virus-induced chronic liver disease: a pilot project. Sci Rep 5:17098

    Article  CAS  Google Scholar 

  4. Yin Y, Wu L, Zhang J, Zhou J, Zhang P, Hou H (2013) Identification of risk factors associated with immunoprophylaxis failure to prevent the vertical transmission of hepatitis B virus. J Infect 66:447–452

    Article  Google Scholar 

  5. Chen Y, Wang L, Xu Y, Liu X, Li S, Qian Q et al (2013) Role of maternal viremia and placental infection in hepatitis B virus intrauterine transmission. Microbes Infect 15:409–415

    Article  Google Scholar 

  6. Delorme-Axford E, Donker RB, Mouillet JF, Chu T, Bayer A, Ouyang Y et al (2013) Human placental trophoblasts confer viral resistance to recipient cells. Proc Natl Acad Sci USA 110:12048–12053

    Article  CAS  Google Scholar 

  7. Xu DZ, Yan YP, Zou S, Choi BC, Wang S, Liu P et al (2001) Role of placental tissues in the intrauterine transmission of hepatitis B virus. Am J Obstet Gynecol 185:981–987

    Article  CAS  Google Scholar 

  8. Bhat P, Anderson DA (2007) Hepatitis B virus translocates across a trophoblastic barrier. J Virol 81:7200–7207

    Article  CAS  Google Scholar 

  9. Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M et al (2004) Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20:337–347

    Article  CAS  Google Scholar 

  10. Li M, Sun XH, Zhu XJ, Jin SG, Zeng ZJ, Zhou ZH et al (2012) HBcAg induces PD-1 upregulation on CD4 + T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients. Lab Invest 92:295–304

    Article  CAS  Google Scholar 

  11. Darmochwal-Kolarz D, Kludka-Sternik M, Kolarz B, Chmielewski T, Tabarkiewicz J, Rolinski J et al (2013) The expression of B7-H1 and B7-H4 co-stimulatory molecules on myeloid and plasmacytoid dendritic cells in pre-eclampsia and normal pregnancy. J Reprod Immunol 99:33–38

    Article  CAS  Google Scholar 

  12. Evans A, Riva A, Cooksley H, Phillips S, Puranik S, Nathwani A et al (2008) Programmed death 1 expression during antiviral treatment of chronic hepatitis B: impact of hepatitis B e-antigen seroconversion. Hepatology 48:759–769

    Article  Google Scholar 

  13. Fisicaro P, Valdatta C, Massari M, Loggi E, Biasini E, Sacchelli L et al (2010) Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 138(682–693):693.e1–693.e4

    Google Scholar 

  14. Das D, Sengupta I, Sarkar N, Pal A, Saha D, Bandopadhyay M et al (2017) Anti-hepatitis B virus (HBV) response of imiquimod based toll like receptor 7 ligand in hbv-positive human hepatocelluar carcinoma cell line. BMC Infect Dis 17:76

    Article  Google Scholar 

  15. Pötgens AJ, Bolte M, Huppertz B, Kaufmann P, Frank HG (2001) Human trophoblast contains an intracellular protein reactive with an antibody against CD133—a novel marker for trophoblast. Placenta 22:639–645

    Article  Google Scholar 

  16. Cui H, Chen J, Na Q (2016) Effect of hepatitis B virus infection on trophoblast cell line (HTR-8/SVneo) and choriocarcinoma cell line (JEG3) is linked to CD133-2 (AC141) expression. Am J Transl Res 8:3235–3240

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tian T, Sun D, Wang P, Wang H, Bai X, Yang X et al (2015) Roles of toll-like receptor 7 and 8 in prevention of intrauterine transmission of hepatitis B virus. Cell Physiol Biochem 37:445–453

    Article  CAS  Google Scholar 

  18. Klaffenbach D, Rascher W, Röllinghoff M, Dötsch J, Meissner U, Schnare M (2005) Regulation and signal transduction of toll-like receptors in human chorioncarcinoma cell lines. Am J Reprod Immunol 53:77–84

    Article  CAS  Google Scholar 

  19. Ding Y, Ma L, Wang XZ, Zhang J, Zhao GZ, Wang ZQ et al (2011) In vitro study on hepatitis B virus infecting human choriocarcinoma JEG3 cells and its mechanism. Intervirology 54:276–281

    Article  Google Scholar 

  20. Boni C, Fisicaro P, Valdatta C, Amadei B, Di VP, Giuberti T et al (2007) Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 81:4215–4225

    Article  CAS  Google Scholar 

  21. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE et al (2006) Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8 + T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol 80:3532–3540

    Article  CAS  Google Scholar 

  22. Otano I, Escors D, Schurich A, Singh H, Robertson F, Davidson BR et al (2018) Molecular recalibration of PD-1 + antigen-specific T cells from blood and liver. Mol Ther 26:2553–2566

    Article  CAS  Google Scholar 

  23. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E et al (2015) Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162:1242–1256

    Article  CAS  Google Scholar 

  24. Okazaki T, Honjo T (2006) The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 27:195–201

    Article  CAS  Google Scholar 

  25. Maier H, Isogawa M, Freeman GJ, Chisari FV (2007) PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8 + T lymphocytes in the liver. J Immunol 178:2714–2720

    Article  CAS  Google Scholar 

  26. Dai S, Jia R, Zhang X, Fang Q, Huang L (2014) The PD-1/PD-Ls pathway and autoimmune diseases. Cell Immunol 290:72–79

    Article  CAS  Google Scholar 

  27. Cho H, Kikuchi M, Li Y, Nakamoto N, Amorosa VK, Valiga ME et al (2014) Induction of multiple immune regulatory pathways with differential impact in HCV/HIV coinfection. Front Immunol 5:265

    Article  Google Scholar 

  28. Noh H, Hu J, Wang X, Xia X, Satelli A, Li S (2015) Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells. Cell Commun Signal 13:14

    Article  Google Scholar 

  29. Chen J, Ji T, Zhao J, Li G, Zhang J, Jin R et al (2016) Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint. Oncotarget 7:41274–41284

    PubMed  PubMed Central  Google Scholar 

  30. Chen N, Fang W, Lin Z, Peng P, Wang J, Zhan J et al (2017) KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma. Cancer Immunol Immunother 66:1175–1187

    Article  CAS  Google Scholar 

Download references

Funding

The study was not supported by any funding.

Author information

Authors and Affiliations

Authors

Contributions

JY, JL, ML: project development, data collection, manuscript writing. MS, XZ: data collection.

Corresponding author

Correspondence to Min Liu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Human or animal studies are not covered in this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, J., Liu, J., Sheng, M. et al. Programmed cell death protein 1 promotes hepatitis B virus transmission through the regulation of ERK1/2-mediated trophoblasts differentiation. Arch Gynecol Obstet 301, 551–558 (2020). https://doi.org/10.1007/s00404-019-05401-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-019-05401-8

Keywords

Navigation