Epstein-Barr Virus Latent Membrane Protein-1 Mediates Upregulation of Tumor Necrosis Factor-α in EBV-Infected T Cells: Implications for the Pathogenesis of Hemophagocytic Syndrome

Abstract

The infection of human T cells by Epstein-Barr virus (EBV) may result in a fatal hemophagocytic syndrome (HS). We have previously shown that EBV can selectively upregulate the tumor necrosis factor-α (TNFα) gene and lead to activation of macrophages in a manner similar to the pathobiology of HS in EBV-infected T lymphoproliferative disorders (LPDs). This study was designed to further clarify the specific EBV gene product(s) responsible for TNFα upregulation. RT-PCR analysis of EBV gene expression was performed on 2 CR2-transfected EBV-infected T lymphoma lines and 2 EBV-infected B cell lines. To identify the EBV gene responsible for upregulation of TNFα, 2 reporter recombinant plasmids, pTNFα-CAT and pTNFα-Luc, were then constructed and cotransfected with the expression plasmids of the EBV latent and lytic genes (EBNA-1, EBNA-2, LMP-1, LMP-2A, and BZLF-1) in both T and B cell lines. Analyses using ELISA and Western blotting were further performed to detect the secreted TNFα. The results revealed that EBNA-1 and LMP-1 were consistently expressed in EBV-infected T cell lines (type II latency), while a type III latency with expression of EBNA-1, EBNA-2, LMP-1, and lytic BZLF transcripts was detected in EBV-infected B cell lines. LMP-1 was demonstrated to be the only EBV gene product to transactivate the TNFα gene, and this phenomenon was observed only in T, not in B, cells. Enhanced secretion of TNF-α protein was also detected in LMP1-transfected T cell lines. We concluded that LMP1 is the candidate protein in the upregulation of the TNFα gene in T cells and is probably responsible for the pathogenesis of HS in EBV-infected T lymphoproliferative disorders.

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

“…The downregulation of miR-125b in the U2932 LMP1 expressors thus might explain how LMP1 activates ERK1/2 and AKT pathway. The TNF-a expression increase by LMP1 (Lay et al, 2003) is consistent with the downregulation of miR-125b, observed here, as this miR targets 3 0 -UTR of TNF-a (Tili et al, 2007).…”

Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome

“…Previously, we demonstrated that EBV infection and LMP1 transfection of T cells could up-regulate TNF-␣. 33,34 In this study, we further demonstrated that LMP1 expression could enhance IFN-␥ secretion. Therefore, both Th1 cytokines TNF-␣ and IFN-␥ could be upregulated by LMP1 expression in T cells.…”

“…[29][30][31][32] The EBV latent membrane protein-1 (LMP1) has been reported to activate T cells, up-regulate tumor necrosis factoralpha (TNF-␣) and interferon-gamma (IFN-␥), and in turn activate macrophages and lead to an enhanced cytokine storm and hemophagocytosis. 16,33,34 Albeit there exist distinct differences for these 2 disease entities as described above, they share common manifestations of dysregulated T-cell activation, enhanced Th1 cytokine secretion, and the subsequent development of fatal HPS. Therefore, the potential involvement of the SAP/SH2D1A molecule in the LMP1-mediated signal pathway in HLH deserves to be elucidated.…”

Biomedical Vignette

“…Where as EBV has been strongly linked to the pathogenesis of this disease, its mode of involvement is not clearly delineated. Lay et al [18] presented evidence indicating that the latent membrane protein-1 of EBV mediates upregulation of tumor necrosis factor-␣ (TNF␣) in T cells, but not in B cells. This enhanced TNF␣ may cooperate with interferon and/or other cytokines in activating macrophage, leading to enhanced hemophagocytosis.…”