EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines

Tsai, Shih‐Chuan; Lin, Shaofu; Chen, Po−Wen; Luo, Wen-Yi; Yeh, Te‐Huei; Wang, Hsei-Wei; Chen, Chi Ju; Tsai, Ching-Hwa

doi:10.1182/blood-2008-12-193375

Cited by 70 publications

(85 citation statements)

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“…Interferon-␥ knockout mice infected with murine herpesvirus (MHV68) develop lung fibrosis and display elevated levels of IL-13 (58). Similar to effects of Zta on IL-13 expression in B cells (79), Zta transcriptionally activates the IL-13 gene in lung epithelial cells. IL-13 promotes collagen synthesis and fibroblast proliferation in vitro and in vivo (28,72), and IL-13 inhibition may reduce lung inflammation and remodeling (8).…”

Section: Discussionmentioning

confidence: 75%

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Modulation of lung inflammation by the Epstein-Barr virus protein Zta

Guenther¹,

Cameron²,

Nguyen³

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Several studies have implicated gamma-herpesviruses, particularly Epstein-Barr virus (EBV), in the progression of idiopathic pulmonary fibrosis. The data presented here examine the possible role that EBV plays in the potentiation of this disease by evaluating the pulmonary response to expression of the EBV lytic transactivator protein Zta. Expression of Zta in the lungs of mice via adenovirus-mediated delivery (Adv-Zta) produced profibrogenic inflammation that appeared most pronounced by day 7 postexposure. Relative to mice exposed to control GFP-expressing adenovirus (Adv-GFP), mice exposed to Adv-Zta displayed evidence of lung injury and a large increase in inflammatory cells, predominantly neutrophils, recovered by bronchoalveolar lavage (BAL). Cytokine and mRNA profiling of the BAL fluid and cells recovered from Adv-Zta-treated mice revealed a Th2 and Th17 bias. mRNA profiles from Adv-Zta-infected lung epithelial cells revealed consistent induction of mRNAs encoding Th2 cytokines. Coexpression in transient assays of wild-type Zta, but not a DNA-binding-defective mutant Zta, activated expression of the IL-13 promoter in lung epithelial cells, and detection of IL-13 in Adv-Zta-treated mice correlated with expression of Zta. Induction of Th2 cytokines in Zta-expressing mice corresponded with alternative activation of macrophages. In cell culture and in mice, Zta repressed lung epithelial cell markers. Despite the profibrogenic character at day 7, the inflammation resolves by 28 days postexposure to Adv-Zta without evidence of fibrosis. These observations indicate that the EBV lytic transactivator protein Zta displays activity consistent with a pathogenic role in pulmonary fibrosis associated with herpesvirus infection.

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Section: Discussionmentioning

confidence: 75%

“…Zta also interacts with several key cellular transcriptional regulatory proteins that affect inflammation including NF-B (61), p53 (53), and the histone acetylase CREBbinding protein (2). Zta-mediated regulation of cellular genes involved in the inflammatory process such as IL-8 (27), IL-13 (79), and TGF-␤ (11,27) has also been demonstrated.…”

mentioning

confidence: 99%

Modulation of lung inflammation by the Epstein-Barr virus protein Zta

Guenther¹,

Cameron²,

Nguyen³

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It had been shown that Epstein-Barr Virus plays an important role in pathogenesis of HL [22][23][24] . Moreover, Tsai and colleagues 25 have determined a relationship between IL-13 and the EBV ZTA protein in both cell lines as well as EBV infected lymphoblastoid cell lines and suggested a contribution of the increased expression of IL-13 in HL's pathogenesis. Formerly, we had determined a previous EBV infection rate of approximately 90% in patients with HL and BL treated in our center 26,27 .…”

Section: Resultsmentioning

confidence: 99%

Serum IL-13 levels at diagnosis and remission in children with malignant lymphoma

et al. 2016

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Interleukin (IL)-13 has been reported to have a role in the pathogenesis of lymphoma through recent molecular studies predominantly in adult patients. As malignant lymphomas in children differ from adult counterparts in terms of histology and response to treatment, we aimed to determine the serum IL-13 levels of patients with lymphoma; its relation with clinical-laboratory parameters and to look for any correlation of serum IL-13 levels with different prognostic factors in children. Twenty-eight patients with malignant lymphoma and 20 age-matched healthy controls were included in the study. The median serum IL-13 level at diagnosis (range 0.59-68 pg/ml, median 3.40 pg/ml) was higher than that in remission (range 0.14-12.2 pg/ml, median 1.60 pg/ml) in the HL group (p<0.05). Remarkably, median serum IL-13 level of patients with nodular sclerosis at diagnosis was higher than those with mixed-cellularity (p<0.05) and declined to normal limits during remission (p<0.05). In Burkitt's lymphoma (BL) subgroup, the median (range 2.94-154 pg/ml, median 4.5 pg/ml) was high and declined to normal levels during remission (range 0.55-11.30 pg/ml, median 1.57 pg/ml) and the difference was significant (p<0.05). In terms of prognostic factors, serum IL-13 levels were found to be associated with white blood cells counts only in HL group. Although the number of patients is limited in our study, we found that the serum IL-13 levels exhibit variances in different histopathologic groups. IL-13 might have a role in histopathogenesis of lymphoma, but seems to have no prognostic significance. Nevertheless, more molecular studies are needed to evaluate the pathogenesis of HL.

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“…Transfection of DNA into cells was performed using TrasIT-LT1 Transfection Reagent (Mirus) according to the manufacturer's instructions. The methods for production and infection of lentiviruses were performed as our previous description (22). Briefly, 0.5 mg p8.91, 1 mg pMD2.G, and 1.5 mg pCMSCV vector or pCMSCV-FLAG-RUNX1b were cotransfected into 1.2 Â 10 6 HEK293T cells.…”

Section: Mutational Analysismentioning

confidence: 99%

“…After 24 hours, the cells were transfected with 0.5 mg pCR3-CBFb combined with 0.5 mg expression plasmids of either wild-type (wt)-RUNX1b, its mutants, or control vector, pcDNA, respectively. The nuclear extracts of the cells were harvested as previously described (22) and applied for electrophoretic mobility shift assay (EMSA) by using the LightShift Chemiluminescent EMSA Kit (Thermo scientific) according to the manufacturer's instructions. Briefly, both forward and reverse strands of the oligonucleotides were labeled with biotin at the 5 0 ends and annealed together to form a double strand probe.…”

Section: Electrophoretic Mobility Shift Assaymentioning

confidence: 99%

Biological Activities of RUNX1 Mutants Predict Secondary Acute Leukemia Transformation from Chronic Myelomonocytic Leukemia and Myelodysplastic Syndromes

Tsai

Shih

Liang

et al. 2015

Clinical Cancer Research

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Purpose: Transcription factor RUNX1 is essential for normal hematopoiesis. High mutation frequencies of RUNX1 gene in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) have been described, whereas the biologic significances of the mutations were not investigated. Here, we aimed to correlate the biologic activities of the RUNX1 mutants with the clinical outcomes of patients.Experimental Design: We examined the mutational status of RUNX1 in 143 MDS and 84 CMML patients. Then, we studied the DNA and CBFb binding abilities of all the RUNX1 mutants identified by using electrophoretic mobility shift assay and coimmunoprecipitation assay, and also determined their activities on target C-FMS gene induction by Western blotting and luciferase reporter assay. Using luciferase reporter assay, the relative biologic activities of each RUNX1 mutant could be quantified and correlated with the patient outcomes by statistical analyses. Results:We observed that most RUNX1 mutants had reduced abilities in DNA binding, CBFb heterodimerization, and C-FMS gene induction. The relative biologic activities of RUNX1 mutants were grouped into high-and low-activity mutations. Correlation of the activities of RUNX1 mutants with the clinical outcomes revealed that patients harboring lower activities of RUNX1 mutants had a higher risk and shorter time to secondary acute myeloid leukemia transformation in MDS and CMML. In multivariate analysis, low RUNX1 activity remained an independent predictor for secondary acute myeloid leukemia-free survival in MDS patients.Conclusions: The biologic activity rather than the mutational status of RUNX1 might be an indicator in predicting outcome of patients with MDS and CMML.

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EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines

Cited by 70 publications

References 50 publications

Modulation of lung inflammation by the Epstein-Barr virus protein Zta

Modulation of lung inflammation by the Epstein-Barr virus protein Zta

Serum IL-13 levels at diagnosis and remission in children with malignant lymphoma

Biological Activities of RUNX1 Mutants Predict Secondary Acute Leukemia Transformation from Chronic Myelomonocytic Leukemia and Myelodysplastic Syndromes

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