Kung-Chao Chang1, Paul C-H Chen2, Yao Chang3, Yu-Hsuan Wu4, Ya-Ping Chen5, Chien-Hsien Lai6, L Jeffrey Medeiros7, Ih-Jen Su3, Hsei-Wei Wang4. 1. Department of Pathology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan. 2. Department of Pathology, Veterans General Hospital-Taipei, Taipei, Taiwan. 3. National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan. 4. Department of Life Sciences, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. 5. Department of Internal Medicine, College of Medicine, National Cheng Kung University and Hospital, Taipei, Taiwan. 6. Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan. 7. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
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.
Authors: Icela Palma-Lara; Ana Elena Sánchez-Aldana; Elva Jiménez-Hernández; Octavio Martínez-Villegas; Juan Carlos Núñez-Enríquez; Juan Manuel Mejía-Aranguré; Sara A Ochoa; Juan Xicohtencatl-Cortes; Ariadnna Cruz-Córdova; Sergio Zavala-Vega; Mariana García-Jiménez; Alejandra Contreras-Ramos; José Refugio Torres-Nava; Guillermo Mora-Ramiro; José Arellano-Galindo Journal: Microorganisms Date: 2020-06-26