title: Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome.
abstract: A potentially fatal hemophagocytic syndrome has been noted in patients with malignant lymphomas, particularly in EBV-infected T cell lymphoma. Cytokines, such as interferon-gamma (IFN-gamma), TNF-alpha, and IL-1alpha, are elevated in patients' sera. To verify whether infection of T cells by EBV will upregulate specific cytokine genes and subsequently activate macrophages leading to hemophagocytic syndrome, we studied the transcripts of TNF-alpha, IFN-gamma, and IL-1alpha in EBV-infected and EBV-negative lymphoma tissues. By reverse transcription PCR analysis, transcripts of TNF-alpha were detected in 8 (57%) of 14 EBV-infected T cell lymphomas, higher than that detected in EBV-negative T cell lymphoma (one of six, 17%), EBV-positive B cell lymphoma (two of five, 40%) and EBV-negative B cell lymphomas (one of seven, 14%). Transcripts of IFN-gamma were consistently detected in T cell lymphoma and occasionally in B cell lymphoma, but were independent of EBV status. IL-1alpha expression was not detectable in any category. Consistent with these in vivo observations, in vitro EBV infection of T cell lymphoma lines caused upregulation of TNF-alpha gene, and increased secretion of TNF-alpha, but not IFN-gamma or IL-1alpha. Expression of TNF-alpha, IFN-gamma, and IL-1alpha was not changed by EBV infection of B cell lymphoma lines. To identify the specific cytokine(s) responsible for macrophage activation, culture supernatants from EBV-infected T cells were cocultured with a monocytic cell line U937 for 24 h. Enhanced phagocytosis and secretion of TNF-alpha, IFN-gamma, and IL-1alpha by U937 cells were observed, and could be inhibited to a large extent by anti-TNF-alpha (70%), less effectively by anti-IFN-gamma (31%), but almost completely by the combination of anti-TNF-alpha and anti-IFN-gamma (85%). Taken together, the in vivo and in vitro observations suggest that infection of T cells by EBV selectively upregulates the TNF-alpha expression which, in combination with IFN-gamma and probably other cytokines, can activate macrophages. This study not only highlights a probable pathogenesis for virus-associated hemophagocytic syndrome, but also suggests that anti-TNF-alpha will have therapeutic potential in the context of their fatal syndrome.
authors.affiliation: Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan 100.
authors.forename: J D
authors.initials: JD
authors.lastname: Lay
authors.forename: C J
authors.initials: CJ
authors.lastname: Tsao
authors.forename: J Y
authors.initials: JY
authors.lastname: Chen
authors.forename: M E
authors.initials: ME
authors.lastname: Kadin
authors.forename: I J
authors.initials: IJ
authors.lastname: Su
mesh_terms: D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006566:Herpesviridae Infections / Q000150:complications*; D015616:Histiocytosis, Non-Langerhans-Cell / Q000150:complications / Q000209:etiology* / Q000276:immunology / Q000821:virology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000150:complications* / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D010587:Phagocytosis; D013601:T-Lymphocytes / Q000821:virology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014412:Tumor Virus Infections / Q000150:complications*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha