High Levels of EBV-Encoded RNA 1 (EBER1) Trigger Interferon and Inflammation-Related Genes in Keratinocytes Expressing HPV16 E6/E7

PLoS One. 2017 Jan 5;12(1):e0169290. doi: 10.1371/journal.pone.0169290. eCollection 2017.

Abstract

Different types of cells infected with Epstein-Barr virus (EBV) can release exosomes containing viral components that functionally affect neighboring cells. Previously, we found that EBV was localized mostly in infiltrating lymphocytes within the stromal layer of cervical lesions. In this study, we aimed to determine effects of exosome-transferred EBV-encoded RNAs (EBERs) on keratinocytes expressing human papillomavirus (HPV) 16 E6/E7 (DonorI-HPV16 HFKs). Lipid transfection of in vitro-transcribed EBER1 molecules (ivt EBER1) into DonorI-HPV16 HFKs caused strong induction of interferon (IFN)-related genes and interleukin 6 (IL-6). To gain insights into the physiological situation, monocyte-derived dendritic cells (moDCs), low passage DonorI-HPV16 HFKs and primary keratinocytes were used as recipient cells for internalization of exosomes from wild-type EBV (wt EBV) or B95-8 EBV-infected lymphoblastoid cell lines (LCLs). qRT-PCR was used to determine the expression of EBER1, HPV16 E6/E7, IFN-related genes and IL-6 in recipient cells. The secretion of inflammatory cytokines was investigated using cytometric bead array. Wt EBV-modified exosomes induced both IFN-related genes and IL-6 upon uptake into moDCs, while exosomes from B95-8 EBV LCLs induced only IL-6 in moDCs. Internalization of EBV-modified exosomes was demonstrated in DonorI-HPV16 HFKs, yielding only EBER1 but not EBER2. However, EBER1 transferred by exosomes did not induce IFN-related genes or IL-6 expression and inflammatory cytokine secretion in DonorI-HPV16 HFKs and primary keratinocytes. EBER1 copy numbers in exosomes from wt EBV-infected LCLs were 10-fold higher than in exosomes from B95-8 LCLs (equal cell equivalent), whereas ivt EBER1 was used at approximately 100-fold higher concentration than in exosomes. These results demonstrated that the induction of IFN-related genes and IL-6 by EBER1 depends on quantity of EBER1 and type of recipient cells. High levels of EBER1 in cervical cells or infiltrating dendritic cells may play a role in the inflammation-to-oncogenesis transition of HPV-associated cervical cancer through modulation of innate immune signals.

MeSH terms

  • Blotting, Western
  • Cell Line
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Exosomes / genetics
  • Exosomes / metabolism
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / metabolism*
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • Interferons / genetics
  • Interferons / metabolism*
  • Keratinocytes / metabolism*
  • Oncogene Proteins, Viral / genetics*
  • Oncogene Proteins, Viral / metabolism*
  • Papillomavirus E7 Proteins / genetics*
  • Papillomavirus E7 Proteins / metabolism*
  • RNA, Viral / metabolism*
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism*

Substances

  • E6 protein, Human papillomavirus type 16
  • Epstein-Barr virus encoded RNA 1
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • RNA, Viral
  • Repressor Proteins
  • oncogene protein E7, Human papillomavirus type 16
  • Interferons

Grants and funding

This work was supported by the Thailand Research Fund and Khon Kaen University through the Royal Golden Jubilee Ph.D. Program (grant no. PHD/0193/2552) (http://rgj.trf.or.th/main/home/) and by the National Research Council of Thailand (grant no. PK/2556-88) (http://en.nrct.go.th/en/home.aspx). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.