Epstein-Barr virus (EBV) latent membrane protein-1 down-regulates tumor necrosis factor-alpha (TNF-alpha) receptor-1 and confers resistance to TNF-alpha-induced apoptosis in T cells: implication for the progression to T-cell lymphoma in EBV-associated hemophagocytic syndrome.
The infection of T cells by Epstein-Barr virus (EBV) may result in hemophagocytic syndrome (HPS) through enhanced cytokine secretion, particularly tumor necrosis factor-alpha (TNF-alpha), by EBV latent membrane protein-1 (LMP-1). One bewildering observation of HPS patients is relapsing disease or progression to T-cell lymphoma. This finding raises the question whether EBV LMP-1-expressing T cells may survive and proliferate in the cytokine milieu of HPS. To explore this possibility, we tested the sensitivity of LMP-1-expressing T cells to apoptosis in the presence of TNF-alpha. LMP-1 up-regulated TNF-alpha through TRAF2,5 and nuclear factor-kappaB pathway in T cells. The LMP-1-expressing T cells then became resistant to TNF-alpha-induced apoptosis. Interestingly, the expression of TNFR1 was remarkably down-regulated by LMP-1 in T cells. Furthermore, the TNF-alpha/TNFR1 downstream death signal TNFR1-associated death domain protein was constitutively recruited by LMP-1, and the activities of apoptotic caspases 3, 8, and 9 were suppressed. Reconstitution of TNFR1 successfully reversed the TNF-alpha-induced apoptotic cascades. Therefore, EBV LMP-1 not only activates T cells to proliferate but also confers resistance to TNF-alpha-mediated apoptosis via down-regulation of TNFR1 in the cytokine milieu of HPS. This finding provides a potential mechanism to explain the disease persistence or progression to T-cell lymphoma in HPS patients.
Chuang
Huai-Chia
HC
Division of Clinical Research, National Health Research Institutes, Taipei, Taiwan.
Lay
Jong-Ding
JD
Chuang
Shuang-En
SE
Hsieh
Wen-Chuan
WC
Chang
Yao
Y
Su
Ih-Jen
IJ
D017209:Apoptosis / Q000502:physiology*; D018450:Disease Progression; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D051359:Lymphohistiocytosis, Hemophagocytic / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016328:NF-kappa B / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins