STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Abstract

IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus of the Lymphocryptovirus genus that has succeeded to colonize Ͼ 90% of the adult population. 1 As a general characteristic of these viruses, they can all infect and immortalize B-lymphocytes in vitro. The in vitro EBV-infected B cells proliferate and give rise to lymphoblastoid cell lines (LCLs). The pattern of latent EBV gene expression seen in LCLs is referred to as the type III latency, in which 9 virally encoded proteins are expressed (EBV nuclear antigen 1-6 [EBNA1-6], Latent Membrane Protein-1 [LMP-1], LMP-2A, and LMP-2B). 1 Similarly to the EBV gene expression seen in LCLs, type III latent B cells were found in healthy persons during the primary infection 2 and the virus carrier state. 3 These cells are highly immunogenic and are eliminated by the cellular immune response. 4 After the primary infection the virus establishes a life-long infection in the memory B-cell reservoir, from where it is thought to reactivate and produce new progeny that are shed in the saliva. 1,5 In immunodeficient states, in which the cellular immune responses are compromised, the EBV-infected type III B cells can give rise to lymphoproliferations/lymphomas, as seen in the posttransplantation lymphoproliferations 6,7 and some AIDS lymphomas. 8 Depending on the histologic origin, the activation state, and the differentiation stage of the virus-carrying cells, EBV can adopt other viral gene expression patterns as well. 9 This is evidenced by the type I EBV gene expression seen in Burkitt lymphomas (BLs), primary effusion lymphomas, 10 and diffuse large B-cell lymphomas, whereby EBNA-1 is the only viral protein expressed. However, EBNA-1 is coexpressed with LMP-1 and LMP-2 in the EBV-carrying classical HL (cHL 11 ; type II latency), nasal natural killer/T-cell lymphoma, 12,13 some nasopharyngeal carcinomas (NPCs), 14,15 and peripheral T-cell lymphomas. 16 The expression of LMP-1 in type III latency is driven by the EBNA-2 protein. 1 The molecular mechanism of LMP-1 expression in type II latent cells, thus in the absence of EBNA-2, is only partially known. EBV-positive cHL is unique among the type II malignancies because all the Hodgkin/Reed-Sternberg (HRS) cells express high levels of LMP-1, whereas LMP-1 expression is heterogeneous in other tumors. 15 Not just the mechanism of LMP-1 expression in the HRS cells is unknown, but it is still an open question whether LMP-1 is needed for the survival or proliferation of these malignant cells. Although the type II EBV latency is seen in a proportion of cHLs, the available HL-derived cell lines are EBV negative. Thus, there is no in vitro system in which this type of virus-cell interaction can be studied.We have previously reported that exposure of the in vitro EBV-converted HL-derived cell line KMH2-EBV to CD40 ligand (CD40L) and interleukin-4 (IL-4) led to EBNA-2-independent expression of LMP-1. 17 In the continuation of this work we identify now IL-4, IL-13, and CD40L as potent inducers of LMP-1 not only Submitted January 21, 2010...

T Cells Modulate Epstein-Barr Virus Latency Phenotypes during Infection of Humanized Mice

“…LMP1 is induced by CD4 ϩ T cell-derived cytokines like IL-4, IL-10, IL-13, and IL-21 (18)(19)(20), which is probably the mechanism through which the T cells provide help for the in vitro growth of the infected B cells. IL-6 is another cytokine known to be a growth factor for EBV-infected B cells (43).…”

“…For survival and proliferation of the EBV-carrying type IIa cells, inter-actions with the microenvironment are required (17). Results from our laboratory have shown that a number of cytokines (interleukin-4 [IL-4], IL-13, and IL-21) contribute to the induction of expression of LMP1 (18)(19)(20) and probably help the survival and proliferation of latency IIa cells in vivo.…”

Induction of Epstein-Barr Virus Oncoprotein LMP1 by Transcription Factors AP-2 and Early B Cell Factor

“…Cytokines, such as interleukin-4 (IL-4), IL-6, IL-10, IL-13, and IL-21, have been frequently reported to activate the JAK/ STAT pathway, thereby inducing LMP1 gene expression through STAT (23)(24)(25)(26)(27)(28). In certain latency II infected cells, including NPC cells (29), LMP1 transcription originates from a STAT regulated upstream promoter, termed TR-L1p, located within the terminal repeats (TRs), in addition to the proximal ED-L1p (23,24,27,30,31). We previously identified a CCAAT enhancer-binding protein (C/EBP) family transcription factor that augments both proximal and distal promoter activation of LMP1 in type II latency by binding to a sequence motif in the proximal promoter (32).…”

Latency Type-Dependent Modulation of Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Expression by Type I Interferons in B Cells

“…LMP-1 plays a central role in EBV biology, since it acts in part as a constitutively active CD40 receptor analog and is essential for B cell proliferation and transformation by EBV (24). In type III latency, EBNA-2 is the major transactivator of the LMP promoters, while in type II latency, depending on the cellular context, different cytokines , are responsible for the activation of LMP-1 transcription (20,26,27,28).Type I interferons (IFNs) are produced in relatively large amounts in response to pathogen sensing by the innate immune system (46). In addition to their direct antiviral activities, these proteins also have antiproliferative and immunomodulatory properties.…”