The epstein‐barr virus latent membrane protein‐1 (LMP1) induces interleukin‐10 production in burkitt lymphoma lines

Nakagomi, Hiroshi; Dolcetti, Riccardo; Bejarano, Maria Teresa; Pisa, Pavel; Kiessling, Rolf; Masucci, Maria G.

doi:10.1002/ijc.2910570218

Cited by 132 publications

(92 citation statements)

References 22 publications

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“…In B-lymphocytes, LMP1 is able to upregulate a number of cellular genes, including the apoptosisinhibiting bcl-2 gene (Henderson et al, 1991;Wang et al, 1996) as well as inducing IL-10, a potent inhibitor of T cell activation (Nakagomi et al, 1994). The transforming effects of LMP1 and its particularly high level expression in the HRS cells of EBV-associated HD indicate a role for this protein in the pathogenesis of EBV-positive HD and suggest important biological differences in HD that may be dependent upon EBV status (Oudejans et al, 1997).…”

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confidence: 99%

Assessment of the prognostic impact of the Epstein–Barr virus-encoded latent membrane protein-1 expression in Hodgkin’s disease

et al. 2001

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SummaryWe have examined expression of the Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) in the malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD) and its impact on response to treatment and on survival. Paraffin tissue from 100 adult immunocompetent patients with HD were analysed using immunohistochemistry to identify LMP1 expression. According to the Rye classification, 8% of patients had lymphocyte predominance (LP) subtype, 48% had nodular sclerosis (NS) disease, 37% were of the mixed cellularity (MC) subtype and 7% were of the lymphocyte depletion (LD) subtype. During the five year follow-up period 27 patients died and 74 patients achieved a complete remission. Patients with LD subtype were older (P = 0.03), less frequently achieved complete remission (P = 0.01), had shorter disease-free survival (P = 0.01) and overall survival (P = 0.002) compared with the other subtypes of HD. LMP1 expression was found in the tumour cells of 26% of cases of HD. LMP1 expression was less common in NS disease than in the other subtypes (P = 0.05), whereas an association between MC subtype and LMP1 expression was not found (P = 0.22). Using the log-rank test there were no differences in overall survival or disease-free survival based on EBV status either when all patients were analysed or when LD and LP subtypes were excluded. However, the presence of EBV was associated with significantly longer disease-free survival in the subgroup of patients ≤ 30 years old (P = 0.02) and in those patients ≤ 34 years old (P = 0.05). In contrast, there was a trend for shorter disease-free survival for EBV-positive patients in the subgroup > 35 years old, but this difference was not statistically significant (P = 0.11). A similar trend was observed in patients > 50 years old. Analysis of the impact of LMP1 expression in patients who had different stage and B symptoms status showed that expression of EBV was associated with longer disease-free survival (P = 0.019) in early stage (1 + 2) patients without B symptoms. Significant differences in the other subgroups based on EBV status was not found. Factors adversely affecting the likelihood to achieve a complete remission were: absence of LMP1 expression (OR 6.4, 95% Cl 1.07-38.5, P = 0.04), age (OR 1.68, 95%Cl 1.15-2.5, P = 0.007) and subtype of HD (OR 3.32, 95%Cl 1.11-9.94, P = 0.03). Age and subtype of HD had an independent impact on overall survival (P = 0.01). We conclude that expression of LMP1 in HRS cells has a favourable impact on prognosis for HD patients, but that this effect may be restricted to young adult patients and those with early stage disease.

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Assessment of the prognostic impact of the Epstein–Barr virus-encoded latent membrane protein-1 expression in Hodgkin’s disease

et al. 2001

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“…28,34 It has been shown also that LMP1 alone is able to induce IL-10 in BL cells but the signaling cascades involved are not known. 16 The precise mechanisms are not yet fully understood. However it has been described that LMP1 triggers NF B and JNK/AP1 activities but clear links of the activation of both signal cascades to the known EBV-activated cellular genes are so far missing.…”

Section: Discussionmentioning

confidence: 99%

“…2 It has been shown that in contrast to normal hematopoietic cells, in EBV-immortalized B cells, EBV-positive Burkitt's lymphoma (BL) cells and in CD40 stimulated B cells, IL-10 is expressed. 6,[13][14][15][16] However, the mechanism of the IL-10 induction in B cells is still unclear. 15,17,18 IL-10 induction by stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) was found to be TNF and cAMP-dependent and shows large interindividual variations.…”

Section: Introductionmentioning

confidence: 99%

“…14,15,17,25 In contrast, most EBV-negative BL cell lines do not express IL-10. [14][15][16]25 The infection of normal B cells with EBV leads to an immortalization of these cells and the expression of IL-10 in vitro. 13 EBV, a ␥-herpesvirus, is detectable in a number of tumours including BL, Hodgkin's disease and nasopharyngeal carcinomas.…”

Section: Introductionmentioning

confidence: 99%

“…28,[31][32][33][34][35] The expression of EBV LMP1 in BL cells, or HTLV-I tax in Jurkat cells induces IL-10 expression. 16,36 Recently, it has been shown that three of the NF B sites were able to bind NF B in HTLV tax expressing human T cell lines, implicating a direct involvement of this transcription factor in virusassociated IL-10 expression. 36 It has been suggested that the activation of NF B by HTLV-I tax is the major cofactor for IL-10 activation.…”

Section: Introductionmentioning

confidence: 99%

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The AT-rich region between −54 to −66 is important for the promoter activity of interleukin-10 in Epstein–Barr virus positive Burkitt’s lymphoma cells

et al. 1999

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IL-10 is an important regulatory cytokine. The recent characterization of the 5Ј-flanking region of IL-10 led to the identification of the promoter region. The infection of B cells with EBV induces IL-10 production which may contribute to EBV-induced transformation. In the present report, IL-10 promoter elements involved in the constitutive expression of IL-10 in EBV-positive lymphoma cells are described. The AT-rich region between −54/−66 from the transcriptional start site was found to be important for IL-10-promoter activity in BL36. A point mutation at position −60 (T/A) was associated with over 90% reduction of luciferase activity in the cell lines BL36 and BL74. The conversion of A/T at position −57 led to enhanced promoter activity. In addition the AT-rich region could serve as an enhancer for the ␤-globin basic promoter. In BJAB cells (EBV-negative), sequences between −205/−139 rather than the AT-rich region were involved in IL-10 promoter regulation. This underlines the importance of the AT-rich region for EBV-associated IL-10 promoter regulation. Our results further the understanding of how the IL-10 gene could be regulated in B cell lymphomas.

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Epstein-Barr virus infection and associated products (LMP, EBNA2, vIL-10) in nodal non-Hodgkin's lymphoma of human immunodeficiency virus-negative Japanese

et al. 1996

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Sixty cases of B-cell nodal nonHodgkin's malignant lymphoma (B-ML), and 46 cases of T-cell nodal lymphoma (T-ML) were surveyed for Epstein-Barr virus (EBV) genomes, RNA, and associated proteins. We used a Southern blot analysis, polymerase chain reaction (PCR), and EBV-encoded small RNA-1 (EBER-1) in situ hybridization to investigate the presence of EBV. We performed an imrnunohistochernical study on EBV-related oncopro-teins, such as EBV-determined nuclear antigen9 (EBNA-2), latent membrane protein (LMP), and viral interleukin-10 (vlL-10). In addition, we also analyzed the terminal repetitive sequence of EBV (EBV-TR) to investigate the EBV-infected cell clonality. Non-Hodgkin's lymphomas were grouped into three types by number of EBV-infected cells: I) almost all lymphoma cells showed an EBV presence; II) some scattered lymphoma cells showed an EBV presence; and 111) only a few cells showed such a presence, which was probably due to a latent EBV infection. In 25 of 60 B-MLs, EBV-infected cells were found; 7 were type I, 1 was type II, and 17 were type 111. In 27 of 46 T-MLs, EBV-infected cells were found; no cases were type I, 5 cases were type II, and 22 cases were type 111. Seven B-MLs and 3 T cell lymphomas showed clonal TR bands. Expression of EBNA-2 was found in only three B-MLs, whereas LMP was seen in four B-MLs and six T-MLs. All EBNA-ZLMP-positive cases showed an EBV presence. In B-MLs, expression of EBNA-2 and LMP was detected in almost all lymphoma cells: in T-MLs, however, LMP was found in only a small portion of the lymphoma cells. Expression of IL-10 was closely associated with LMP. In summary, it was thus speculated that EBV infection was associated with the various states of lymphomagenesis.

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The epstein‐barr virus latent membrane protein‐1 (LMP1) induces interleukin‐10 production in burkitt lymphoma lines

Cited by 132 publications

References 22 publications

Assessment of the prognostic impact of the Epstein–Barr virus-encoded latent membrane protein-1 expression in Hodgkin’s disease

Assessment of the prognostic impact of the Epstein–Barr virus-encoded latent membrane protein-1 expression in Hodgkin’s disease

The AT-rich region between −54 to −66 is important for the promoter activity of interleukin-10 in Epstein–Barr virus positive Burkitt’s lymphoma cells

Epstein-Barr virus infection and associated products (LMP, EBNA2, vIL-10) in nodal non-Hodgkin's lymphoma of human immunodeficiency virus-negative Japanese

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