UP-REGULATION 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

A potentially fatal hemophagocytic syndrome has been noted in patients with malignant lymphomas, particularly in EBV-infected T cell lymphom a, Cytokines, such as interferon-gamma (IFN-gamma), TNF-alpha, and IL- 1 alpha, are elevated in patients' sera. To verify whether infection o f T cells by EBV will upregulate specific cytokine genes and subsequen tly activate macrophages leading to hemophagocytic syndrome, we studie d the transcripts of TNF-alpha, IFN-gamma, and IL-1 alpha in EBV-infec ted and EBV-negative lymphoma tissues, By reverse transcription PCR an alysis, transcripts of TNF-alpha were detected in 8 (57%) of 14 EBV-in fected T cell lymphomas, higher than that detected in EBV-negative T c ell lymphoma (one of six, 17%), EBV-positive B cell lymphoma (two of f ive, 40%) and EBV-negative B cell lymphomas (one of seven, 14%). Trans cripts of IFN-gamma were consistently detected in T cell lymphoma and occasionally in B cell lymphoma, but were independent of EBV status. I L-1 alpha expression was not detectable in any category. Consistent wi th these in vivo observations, in vitro EBV infection of T cell lympho ma lines caused upregulation of TNF-alpha gene, and increased secretio n of TNF-alpha, but not IFN-gamma or IL-1 alpha. Expression of TNF-alp ha, IFN-gamma, and IL-1 alpha was not changed by EBV infection of B ce ll lymphoma lines. To identify the specific cytokine(s) responsible fo r macrophage activation, culture supernatants from EBV-infected T cell s were cocultured with a monocytic cell line U937 for 24 h. Enhanced p hagocytosis and secretion of TNF-alpha, IFN-gamma, and IL-1 alpha by U 937 cells were observed, and could be inhibited to a large extent by a nti-TNF-alpha (70%), less effectively by anti-IFN-gamma (31%), but alm ost 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 cy tokines, can activate macrophages. This study not only highlights a pr obable pathogenesis for virus-associated hemophagocytic syndrome, but also suggests that anti-TNF-alpha will have therapeutic potential in t he context of their fatal syndrome.