title: 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.
authors: Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States.
authors: Ryan
authors: R
authors: Incrocci
authors: Department of Biomedical Sciences, College of Health Sciences, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States.
authors: Levi
authors: L
authors: Barse
authors: Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States.
authors: Amanda
authors: A
authors: Stone
authors: Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States.
authors: Sai
authors: S
authors: Vagvala
authors: Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States.
authors: Michael
authors: M
authors: Montesano
authors: Department of Biomedical Sciences, College of Health Sciences, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States.
authors: Vijay
authors: V
authors: Subramaniam
authors: Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, United States. Electronic address: mswans@midwestern.edu.
authors: Michelle
authors: M
authors: Swanson-Mungerson
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D050796:STAT3 Transcription Factor; D014763:Viral Matrix Proteins; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human
keywords: B cell; Bruton's tyrosine kinase (BTK); Epstein-Barr virus; Interleukin-10; Latent Membrane Protein 2A; Signal Transducer and Activator of Transcription 3 (STAT3)