EPSTEIN-BARR-VIRUS INDUCES GM-CSF SYNTHESIS BY MONOCYTES - EFFECT ON EBV-INDUCED IL-1 AND IL-1 RECEPTOR ANTAGONIST PRODUCTION IN NEUTROPHILS

Neutrophils play an important role in the control of viral infections by releasing a variety of potent agents. We previously demonstrated th at Epstein-Barr virus (EBV) binds to human neutrophils and stimulates cytokine synthesis including interleukin-1 (IL-l) and IL-l receptor an tagonist (IL-1Ra). Since neutrophil functions are known to be modulate d by the priming effect of granulocyte-macrophage colony-stimulating f actor (GM-CSF), we therefore investigated the cellular source of GMCSF synthesis following treatment of leukocytes with EBV and the effect o f GM-CSF on the production of IL-l, IL-1Ra, and superoxide by EBV-trea ted neutrophils. In enriched-cell populations, only monocytes were fou nd to produce GM-CSF in response to EBV, which was maximal after 12 h of incubation. The results obtained with UV-irradiated particles or EB V neutralized with monoclonal antibody 72A1 suggest that contact betwe en the cell and the gp350 of the viral envelope is sufficient to induc e the release of GM-CSF. On the other hand, GM-CSF differentially upre gulated EBV-induced IL-l and IL-1Ra production by neutrophils. Pretrea tment of neutrophils with GM-CSF prior to EBV activation synergistical ly enhanced the production of IL-l alpha and IL-I beta, but only margi nally affected IL-1Ra synthesis. In addition, GM-CSF was also found to synergistically enhance the superoxide production by neutrophils in r esponse to EBV. Molecular analysis showed that GMCSF did not alter the IL-1 beta and IL-1Ra mRNA synthesis induced by EBV, suggesting that G M-CSF could act at a posttranslational level. Local production of GM-C SF by monocytes in tissues invaded by EBV could serve to potentiate th e host defense mechanisms directed toward the destruction of the infec tious virus. (C) 1997 Academic Press.