Human cytomegalovirus-induced immunosuppression: Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E₂ in human monocytes

Cytomegalovirus (CMV) has been associated with immunesuppression. Previously CMV was reported to interfere with signal transduction pathways in T cells. In this report the mechanisms underlying CMV-mediated immunosuppression were examined. Supernatants of CMV (Strains C-87, AD-169)-infected primary human monocyte (MO) cultures inhibited mitogenic T cell proliferative responses by > 95%. The inhibitory activity was observed 24 h through day 7 postinfection. The infection of MO was associated with a sustained elevation of intracellular levels of cAMP and the release of arachidonic acid (AA) and its metabolite PGE₂ (activator of adenylate cyclase) in culture supernatants. The AA release was incidentally associated with TNF-α production. Monoclonal antibodies to TNF-α and pentoxyphylline (inhibitor of TNF synthesis) inhibited both AA and PGE₂ release. The release of AA required protein synthesis and occurred under conditions consistent with the expression of CMV immediate early genes. Treatment of MO cultures at time of infection with 100 μM indomethacin or 1 μg of TNF-α mAb abolished the CMV-induced T cell inhibitory activity of the supernatants by 100%. These data suggest that TNF dependent release of AA and PGE₂ contributes to CMV-induced immunosuppression.