Journal
HISTOPATHOLOGY
Volume 70, Issue 3, Pages 442-455Publisher
WILEY
DOI: 10.1111/his.13085
Keywords
cytokines; Epstein-Barr virus latent membrane protein-1; Hodgkin lymphoma; old age; poor prognosis
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Funding
- National Science Council, Taiwan [NSC 97-2320-B-006-022-MY3]
- Ministry of Health and Welfare [MOHW105-TDU-B-211-133016]
- Ministry of Science and Technology, Taiwan [MOST-103-2320-B-006-020-MY3]
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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)-1 alpha, MIP-1 beta, and interleukin (IL)-13. Immunostaining of HL samples (n = 104) showed that expression of MIP-1 alpha, MIP-1 beta 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-1 alpha, MIP-1 beta 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-1 alpha, MIP-1 beta 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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