Interleukin-6 and Epstein-Barr virus induction by cyclosporine A: potential role in lymphoproliferative disease.
Posttransplant patients undergoing prolonged cyclosporine A (CsA) immunosuppressive therapy have been reported to have increased incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. We undertook experiments to analyze the possible actions of CsA during EBV-infection of human peripheral blood mononuclear cells (PBMC). EBV-infected B cells cultured with CsA demonstrated increased EBV B-cell outgrowth as compared with those cultured without CsA. PBMC, after infection with EBV and CsA treatment, demonstrated increased interleukin-6 (IL-6) activity in the culture supernatant. The induction of IL-6 appears to differ within the various lymphocyte populations. In monocytes, IL-6 expression appears preferentially induced by EBV and is initiated by the binding of the two major virion glycoproteins, gp350 and gp220. Expression of IL-6 in T cells appears to be due mainly to CsA. B cells also express IL-6 after EBV exposure, but not after CsA treatment. EBV-immortalized B-cell lines cultured with CsA exhibited both an increased number of cells expressing viral lytic-cycle antigens and increased amounts of lytic-cycle proteins. IL-6, which is induced by CsA in PBMC, was also capable of inducing the lytic viral cycle in several EBV-immortalized cells. CsA, in promoting both increased numbers of lytic EBV B cells and an EBV paracrine factor, IL-6, within the microenvironment of EBV B cell:T cell and EBV B cell:monocyte interactions, may result in increased EBV B-cell immortalization and ultimately lead to the promotion of B-cell lymphomas in immunosuppressed patients.
Tanner
J E
JE
Laboratory of Immunovirology, Pediatric Research Center, University of Montréal, Quebéc, Canada.
Menezes
J
J
D000956:Antigens, Viral / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000821:virology; D002472:Cell Transformation, Viral / Q000187:drug effects*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000254:growth & development*; D006801:Humans; D016867:Immunocompromised Host; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D015759:Ionomycin / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000821:virology; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000821:virology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017464:Receptors, Complement 3d / Q000502:physiology; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014412:Tumor Virus Infections / Q000821:virology*; D014763:Viral Matrix Proteins / Q000502:physiology; D014775:Virus Activation / Q000187:drug effects*
D000956:Antigens, Viral; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015850:Interleukin-6; D017464:Receptors, Complement 3d; D014763:Viral Matrix Proteins; D015759:Ionomycin; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate