Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 production through the activation of Bruton's tyrosine kinase and STAT3

Abstract

Previous data demonstrate that Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 to promote the survival of LMP2A-expressing B cell lymphomas. Since STAT3 is an important regulator of IL-10 production, we hypothesized that LMP2A activates a signal transduction cascade that increases STAT3 phosphorylation to enhance IL-10. Using LMP2A-negative and –positive B cell lines, the data indicate that LMP2A requires the early signaling molecules of the Syk/RAS/PI3K pathway to increase IL-10. Additional studies indicate that the PI3K-regulated kinase, BTK, is responsible for phosphorylating STAT3, which ultimately mediates the LMP2A-dependent increase in IL-10. These data are the first to show that LMP2A signaling results in STAT3 phosphorylation in B cells through a PI3K/BTK-dependent pathway. With the use of BTK and STAT3 inhibitors to treat B cell lymphomas in clinical trials, these findings highlight the possibility of using new pharmaceutical approaches to treat EBV-associated lymphomas that express LMP2A.

Epstein‐Barr virus LMP2A utilizes Syk and PI3K to activate NF‐κB in B‐cell lymphomas to increase MIP‐1α production

“…In combination with the findings reported here, these data suggest the importance of this chemokine in the life cycle of EBV and the development of HL tumor microenvironment. Furthermore, we and others demonstrated that both LMP1 and LMP2A result in the increase of the prosurvival cytokine, IL‐10 . Once again, the two proteins use distinct mechanisms to increase IL‐10: LMP1 uses p38K in addition to PI3K to increase IL‐10, while LMP2A uses the activation of the PI3K/BTK/STAT3 pathway without the need for p38K activation and data presented here).…”

“…Furthermore, we and others demonstrated that both LMP1 and LMP2A result in the increase of the prosurvival cytokine, IL-10. 24,25,55 Once again, the two proteins use distinct mechanisms to increase IL-10: LMP1 uses p38K in addition to PI3K to increase IL-10, 55 while LMP2A uses the activation of the PI3K/BTK/STAT3 pathway without the need for p38K activation 25 and data presented here). Future studies need to address whether the activation of NF-κB is additive when both LMP1 and LMP2A are present, since previous studies indicate that these two proteins can positively affect the signaling of one another.…”

“…These data are the first to demonstrate that LMP2A activates NF‐κB in human B cells and that it regulates a function of B‐cell tumors, namely the production of MIP‐1α. These findings indicate that LMP2A not only directly promotes the survival of HL survival, but may also indirectly promote HL tumor survival through the production of IL‐10 and chemokines such as MIP‐1α.…”

“…19,23,24 For example, we and others have demonstrated that LMP2A specifically increases the production of interleukin 10 (IL-10) 24 through a Syk/Ras/PI3K/STAT3 pathway. 25 However, the influence of LMP2A on chemokine production in EBV-associated malignancies is unknown. In contrast, the ability of BCR signaling to increase chemokine production has been assessed.…”

Effects of BTK signalling in pathogenic microorganism infections

“…LMP2A + Btk −/− mice exhibit an aggravated Xid phenotype compared with that of Btk −/− littermates, including immature phenotypes and decreased B cell numbers during B cell development, whereas the capability of LMP2A is partially restored in the absence of both Btk and RAG‐1, supporting the production of CD19 + IgM − B cells in the bone marrow . Another study demonstrated that LMP2A enhanced STAT3‐mediated IL‐10 production to promote the survival of EBV‐positive B cell lymphomas through the activation of Btk . These findings highlight that Btk is a potential drug target for the treatment of EBV‐associated LMP2A‐expressing B cell lymphomas.…”