Comparative Analysis of Signal Transduction by CD40 and the Epstein-Barr Virus Oncoprotein LMP1 In Vivo

Panagopoulos, Dimitris J.; Victoratos, Panayiotis; Alexiou, Maria; Kollias, George; Mosialos, George

doi:10.1128/jvi.78.23.13253-13261.2004

Cited by 55 publications

(53 citation statements)

References 37 publications

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“…The lack of an LMP1 homolog suggests differential signaling in mouse verses human epithelium. Although expression of LMP1 in transgenic mouse lines targeted to the B cells promotes lymphomas (43) and mimics CD40 signaling (44), similar to the expression seen in humans, expression of LMP1 in murine pulmonary epithelial cells is not analogous to the signaling characteristics of LMP1 expression in human lung epithelial cells, and does not provide an appropriate model for this study.…”

Section: Discussionmentioning

confidence: 84%

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

Sides¹,

Klingsberg²,

Shan³

et al. 2011

Am J Respir Cell Mol Biol

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Idiopathic Pulmonary Fibrosis (IPF) is characterized by thickening of the interstitium due to collagen deposition resulting in destruction of the alveolar architecture. A growing body of evidence suggests lung myofibroblasts are derived from epithelial origin through Epithelial‐Mesenchymal Transition (EMT). TGF‐b induces EMT in lung epithelial cells in a time and dose dependent manner. Higher occurrence of Epstein‐Barr virus (EBV) has been reported in lung tissue of IPF patients compared with that of non‐IPF patients. Our data show a remarkable increase in mesenchymal cell markers with concurrent reduction in the expression of epithelial cell markers in lung epithelial cells co‐treated with LMP‐1 and very low doses of TGF ƒÒ. We show that the pro‐EMT LMP1 signaling is primarily through the NF‐kB pathway and the pro‐EMT TGFb signaling is through the ERK pathway. LMP1 reduces TGFb signaling through Smad2/3 and increases TGFb ERK signaling. Together, these data suggest that the presence of EBV‐LMP1 in lung epithelial cells sensitizes these cells to TGF ƒÒ, synergistically inducing EMT. Our in vitro data may help explain the observation that IPF patients demonstrating positive staining for LMP‐1 in alveolar epithelial cells have a more rapid demise than patients in whom LMP‐1 is not detected.

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Section: Discussionmentioning

confidence: 84%

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

Sides¹,

Klingsberg²,

Shan³

et al. 2011

Am J Respir Cell Mol Biol

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“…What then is the role of LMP1 and LMP2 in the GC? Studies in vitro and from transgenic mice have imputed potent signaling activities to LMP1 and LMP2 (7,8,13,15,35,47), implying that they can, in principle, drive the entire GC process in the absence of antigen and even rescue defective B cells (7,47). However, this does not appear to be happening in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…The same viral transcription program is found in Hodgkin's disease (38), a tumor of the GC (46). LMP1 and LMP2 have been shown to possess, respectively, the CD40 and BCR signaling functions necessary for GC survival (7,8,13,15,35,47), and EBNA1 is required for replication of the viral genome. However, CD10 is only a phenotypic marker of GC cells.…”

mentioning

confidence: 79%

The Intersection of Epstein-Barr Virus with the Germinal Center

Roughan

Thorley‐Lawson

2009

J Virol

134

124

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The current model of Epstein-Barr virus (EBV) infection and persistence in vivo proposes that EBV uses the germinal center (the GC model) to establish a quiescent latent infection in otherwise-normal memory B cells. However, the evidence linking EBV-infected cells and the GC is only indirect and limited. Therefore, a key portion of the model, that EBV-infected cells physically reside and participate in GCs, has yet to be verified. Furthermore, recent experiments suggested that upon infection of GC cells the viral growth latency transcription program is dominant and GC functionality and phenotype are ablated, i.e., EBV infection is not consistent with GC function. In this study we show that in vivo, EBV-infected B cells in the tonsils retain expression of functional and phenotypic markers of GC cells, including bcl-6 and AID. Furthermore, these cells are physically located in the GC and express a restricted form of latency, the default latency program. Thus, the EBV default latency transcription program, unlike the growth latency program, is consistent with the retention of GC functionality in vivo. This work verifies key components of the GC model of EBV persistence and suggests that EBV and the GC can interact to produce the latently infected memory cells found in the periphery. Furthermore, it identifies latently infected GC B cells as a potential pathogenic nexus for the development of the EBV-positive, GC-associated lymphomas Hodgkin's disease and Burkitt's lymphoma.Epstein-Barr virus (EBV) is able to promiscuously and efficiently infect any resting B cell in culture, leading to cellular activation, proliferation, and the outgrowth of transformed lymphoblastoid cell lines (the growth latency transcription program, also known as latency 3) (38, 48). Not surprisingly, the virus is also associated with important human malignancies that include B-cell lymphomas (Burkitt's, Hodgkin's, and immunoblastic lymphomas in the immunosuppressed) and carcinomas (nasopharyngeal and gastric) (38, 50). Despite its pathogenic potential, EBV benignly infects Ͼ90% of the human population and persists for life. A central question in understanding both persistent infection and the origins of EBV-associated cancer is how the host and virus interact to allow benign persistent infection. Specifically, how does this interaction regulate and limit the capacity of the virus to drive cellular growth?An important insight into this question was the discovery that EBV persists in circulating, resting, memory B cells (5, 50) These cells do not express viral proteins (17) and appear to be maintained in the periphery by normal memory B-cell homeostasis mechanisms, not by the growth-promoting activity of the virus (44). Consequently, they are not a pathogenic risk to the host nor are they subject to immunosurveillance and can therefore persist benignly within the human host for decades.The mechanism by which EBV gains access to the memory B cell remains controversial. The most widely held model is that the virus uses the growth latency program ...

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“…The constitutive activation of this signaling pathway was proven in vivo in transgenic mice expressing chimeric LMP1/CD40 with the transmembrane domains of LMP1 fused to the carboxy signaling domains of CD40 (Panagopoulos et al, 2004). These mice had dramatic upregulation of CD69, CD80, and CD86, which are known targets of CD40 signaling, and greatly increased serum IgM.…”

Section: Introductionmentioning

confidence: 98%

LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

et al. 2005

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Transgenic mice expressing Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) under the control of an immunoglobulin heavy-chain promoter and enhancer develop lymphoma at a threefold higher incidence than LMP1-negative mice. In vitro, LMP1 activates numerous signaling pathways including p38, c-Jun N terminal kinase (JNK), phosphatidylinositol 3 kinase (PI3K)/Akt, and NF-jB through interactions with tumor necrosis receptorassociated factors (TRAFs). These pathways are frequently activated in EBV-associated malignancies, although their activation cannot be definitively linked to LMP1 expression in vivo. In this study, interactions between LMP1 and TRAFs and the activation of PI3K/ Akt, JNK, p38, and NF-jB were examined in LMP1 transgenic mice. LMP1 co-immunoprecipitated with TRAFs 1, 2, and 3. Akt, JNK, and p38 were activated in LMP1-positive and -negative splenocytes as well as LMP1-positive and -negative lymphomas. Multiple forms of NF-jB were activated in healthy splenocytes from LMP1 transgenic mice, in contrast to healthy splenocytes from LMP1-negative mice. However, in both LMP1-positive and -negative lymphomas, only the oncogenic NF-jB c-Rel, was specifically activated. Similarly to EBV-associated malignancies, p53 protein was detected at high levels in the transgenic lymphomas, although mutations were not detected in the p53 gene. These data indicate that NF-jB is activated in LMP1-positive healthy splenocytes; however, NF-jB c-Rel is specifically activated in both the transgenic lymphomas and in the rare lymphomas that develop in negative mice. The LMP1-mediated activation of NF-jB may contribute to the specific activation of c-Rel and lead to the increased development of lymphoma in the LMP1 transgenic mice.

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Comparative Analysis of Signal Transduction by CD40 and the Epstein-Barr Virus Oncoprotein LMP1 In Vivo

Cited by 55 publications

References 37 publications

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

The Epstein-Barr Virus Latent Membrane Protein 1 and Transforming Growth Factor–β1 Synergistically Induce Epithelial–Mesenchymal Transition in Lung Epithelial Cells

The Intersection of Epstein-Barr Virus with the Germinal Center

LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

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