Epstein–Barr virus latent membrane protein-1 up-regulates cytokines and correlates with older age and poorer prognosis in Hodgkin lymphoma

Kung-Chao Chang, Paul C.H. Chen, Yao Chang, Yu Hsuan Wu, Ya-Ping Chen, Chien Hsien Lai, L. Jeffrey Medeiros, Ih Jen Su, Hsei Wei Wang

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Abstract

Aims: Previously, we reported an association between Epstein–Barr virus (EBV)-positive Hodgkin lymphoma (HL), older age, and poorer prognosis. The aim of this study was to investigate the mechanisms underlying this association. Methods and results: Transfection of HL cell lines with EBV latent membrane protein-1 (LMP1) resulted in up-regulation of many cytokine genes as assessed by the use of oligonucleotide microarrays. The up-regulation of cytokines was validated by using an inflammatory cytokine protein array: macrophage inflammatory protein (MIP)-1α, MIP-1β, and interleukin (IL)-13. Immunostaining of HL samples (n = 104) showed that expression of MIP-1α, MIP-1β and IL-13 correlated with EBV infection and LMP1 expression. Combined expression of these cytokines was more common in patients aged >60 years (P < 0.001), and was associated with a poorer prognosis (P = 0.042). In another cohort, serum levels of MIP-1α, MIP-1β and IL-13 were increased in HL patients (n = 53) and highest in EBV-positive HL patients as compared with healthy controls (n = 40). Xenograft mice injected with EBV-positive HL cells had higher serum levels of MIP-1α, MIP-1β and IL-13 than mice injected with EBV-negative HL cells, although there was no difference in growth. Conclusions: EBV infection appears to promote the release of cytokines in HL patients, and negatively impacts on patient survival. Physiological immunosenescence probably explains the association between EBV infection and older age. Cytokine modulation is a potential therapeutic target for EBV-positive HL patients.

Original languageEnglish
Pages (from-to)442-455
Number of pages14
JournalHistopathology
Volume70
Issue number3
DOIs
Publication statusPublished - 2017 Feb 1

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Macrophage Inflammatory Proteins
Hodgkin Disease
Membrane Proteins
Up-Regulation
Cytokines
Viruses
Interleukin-13
Virus Diseases
Protein Array Analysis
Oligonucleotide Array Sequence Analysis
Serum
Heterografts
Transfection
Cell Line
Survival

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Histology

Cite this

Chang, Kung-Chao ; Chen, Paul C.H. ; Chang, Yao ; Wu, Yu Hsuan ; Chen, Ya-Ping ; Lai, Chien Hsien ; Jeffrey Medeiros, L. ; Su, Ih Jen ; Wang, Hsei Wei. / Epstein–Barr virus latent membrane protein-1 up-regulates cytokines and correlates with older age and poorer prognosis in Hodgkin lymphoma. In: Histopathology. 2017 ; Vol. 70, No. 3. pp. 442-455.
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title = "Epstein–Barr virus latent membrane protein-1 up-regulates cytokines and correlates with older age and poorer prognosis in Hodgkin lymphoma",
abstract = "Aims: Previously, we reported an association between Epstein–Barr virus (EBV)-positive Hodgkin lymphoma (HL), older age, and poorer prognosis. The aim of this study was to investigate the mechanisms underlying this association. Methods and results: Transfection of HL cell lines with EBV latent membrane protein-1 (LMP1) resulted in up-regulation of many cytokine genes as assessed by the use of oligonucleotide microarrays. The up-regulation of cytokines was validated by using an inflammatory cytokine protein array: macrophage inflammatory protein (MIP)-1α, MIP-1β, and interleukin (IL)-13. Immunostaining of HL samples (n = 104) showed that expression of MIP-1α, MIP-1β and IL-13 correlated with EBV infection and LMP1 expression. Combined expression of these cytokines was more common in patients aged >60 years (P < 0.001), and was associated with a poorer prognosis (P = 0.042). In another cohort, serum levels of MIP-1α, MIP-1β and IL-13 were increased in HL patients (n = 53) and highest in EBV-positive HL patients as compared with healthy controls (n = 40). Xenograft mice injected with EBV-positive HL cells had higher serum levels of MIP-1α, MIP-1β and IL-13 than mice injected with EBV-negative HL cells, although there was no difference in growth. Conclusions: EBV infection appears to promote the release of cytokines in HL patients, and negatively impacts on patient survival. Physiological immunosenescence probably explains the association between EBV infection and older age. Cytokine modulation is a potential therapeutic target for EBV-positive HL patients.",
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Epstein–Barr virus latent membrane protein-1 up-regulates cytokines and correlates with older age and poorer prognosis in Hodgkin lymphoma. / Chang, Kung-Chao; Chen, Paul C.H.; Chang, Yao; Wu, Yu Hsuan; Chen, Ya-Ping; Lai, Chien Hsien; Jeffrey Medeiros, L.; Su, Ih Jen; Wang, Hsei Wei.

In: Histopathology, Vol. 70, No. 3, 01.02.2017, p. 442-455.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epstein–Barr virus latent membrane protein-1 up-regulates cytokines and correlates with older age and poorer prognosis in Hodgkin lymphoma

AU - Chang, Kung-Chao

AU - Chen, Paul C.H.

AU - Chang, Yao

AU - Wu, Yu Hsuan

AU - Chen, Ya-Ping

AU - Lai, Chien Hsien

AU - Jeffrey Medeiros, L.

AU - Su, Ih Jen

AU - Wang, Hsei Wei

PY - 2017/2/1

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N2 - Aims: Previously, we reported an association between Epstein–Barr virus (EBV)-positive Hodgkin lymphoma (HL), older age, and poorer prognosis. The aim of this study was to investigate the mechanisms underlying this association. Methods and results: Transfection of HL cell lines with EBV latent membrane protein-1 (LMP1) resulted in up-regulation of many cytokine genes as assessed by the use of oligonucleotide microarrays. The up-regulation of cytokines was validated by using an inflammatory cytokine protein array: macrophage inflammatory protein (MIP)-1α, MIP-1β, and interleukin (IL)-13. Immunostaining of HL samples (n = 104) showed that expression of MIP-1α, MIP-1β and IL-13 correlated with EBV infection and LMP1 expression. Combined expression of these cytokines was more common in patients aged >60 years (P < 0.001), and was associated with a poorer prognosis (P = 0.042). In another cohort, serum levels of MIP-1α, MIP-1β and IL-13 were increased in HL patients (n = 53) and highest in EBV-positive HL patients as compared with healthy controls (n = 40). Xenograft mice injected with EBV-positive HL cells had higher serum levels of MIP-1α, MIP-1β and IL-13 than mice injected with EBV-negative HL cells, although there was no difference in growth. Conclusions: EBV infection appears to promote the release of cytokines in HL patients, and negatively impacts on patient survival. Physiological immunosenescence probably explains the association between EBV infection and older age. Cytokine modulation is a potential therapeutic target for EBV-positive HL patients.

AB - Aims: Previously, we reported an association between Epstein–Barr virus (EBV)-positive Hodgkin lymphoma (HL), older age, and poorer prognosis. The aim of this study was to investigate the mechanisms underlying this association. Methods and results: Transfection of HL cell lines with EBV latent membrane protein-1 (LMP1) resulted in up-regulation of many cytokine genes as assessed by the use of oligonucleotide microarrays. The up-regulation of cytokines was validated by using an inflammatory cytokine protein array: macrophage inflammatory protein (MIP)-1α, MIP-1β, and interleukin (IL)-13. Immunostaining of HL samples (n = 104) showed that expression of MIP-1α, MIP-1β and IL-13 correlated with EBV infection and LMP1 expression. Combined expression of these cytokines was more common in patients aged >60 years (P < 0.001), and was associated with a poorer prognosis (P = 0.042). In another cohort, serum levels of MIP-1α, MIP-1β and IL-13 were increased in HL patients (n = 53) and highest in EBV-positive HL patients as compared with healthy controls (n = 40). Xenograft mice injected with EBV-positive HL cells had higher serum levels of MIP-1α, MIP-1β and IL-13 than mice injected with EBV-negative HL cells, although there was no difference in growth. Conclusions: EBV infection appears to promote the release of cytokines in HL patients, and negatively impacts on patient survival. Physiological immunosenescence probably explains the association between EBV infection and older age. Cytokine modulation is a potential therapeutic target for EBV-positive HL patients.

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