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

Aims Previously, we reported an association between Epstein-Barr virus (EBV)-positive Hodgkin lymphoma (HL), older age and poorer prognosis. The mechanisms underlying this association remain unclear. Methods and results Transfection of HL cell lines with EBV-latent membrane protein-1 (LMP1) resulted in upregulation of many cytokine genes as assessed by using oligonucleotide microarrays. Three upregulated cytokines, were validated by using an inflammatory cytokine protein array: MIP-1α, MIP-1β, IL-13. Immunostaining of HL samples (n=104) showed that expression of MIP-1α, MIP-1β, IL-13 correlated with EBV infection and LMP1 expression. Combined expression of these cytokines was more common in patients >60 years (p<0.001) and was associated with poorer prognosis (p=0.042). In another cohort, serum levels of MIP-1α, MIP-1β, and IL-13 were higher in HL patients (n=53) and highest in EBV-positive HL patients compared with healthy controls (n=40). Xenograft mice injected with EBV-positive HL cells had higher serum levels of MIP-1α, MIP-1β, IL-13 compared with 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 patient survival. Physiological immunosenescence likely explains the association between EBV infection and older age. Cytokine modulation is a potential therapeutic target for EBV-positive HL patients. This article is protected by copyright. All rights reserved.