title: Epstein-Barr virus latent membrane protein-1 up-regulates cytokines and correlates with older age and poorer prognosis in Hodgkin lymphoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pathology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan.
authors.forename: Kung-Chao
authors.initials: KC
authors.lastname: Chang
authors.affiliation: Department of Pathology, Veterans General Hospital-Taipei, Taipei, Taiwan.
authors.forename: Paul C-H
authors.initials: PC
authors.lastname: Chen
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, College of Medicine, National Cheng Kung University and Hospital, Taipei, Taiwan.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Chen
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chien-Hsien
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
authors.affiliation: Department of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
mesh_terms: D000328:Adult; D000375:Aging; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology*; D005260:Female; D064593:Heterografts; D006689:Hodgkin Disease / Q000276:immunology / Q000401:mortality / Q000821:virology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D046888:Tissue Array Analysis; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins
keywords: Epstein-Barr virus latent membrane protein-1; Hodgkin lymphoma; cytokines; old age; poor prognosis