Inflammatory cytokines and the reactivation of Kaposi's sarcoma-associatedherpesvirus lyric replication

Kaposi's sarcoma (KS) is a complex proliferative lesion long suspected of b eing dependent on exogenous paracrine signaling molecules to stimulate its proliferative, angiogenic, and inflammatory components. In particular, both clinical and experimental observations have pointed to a potential role fo r inflammatory cytokines as permissive factors for KS development, but KS p athogenesis is also critically dependent on infection by an exogenous herpe svirus, the KS-associated herpesvirus (KSHV). To examine the possible links between inflammatory cytokines and KSHV replication, we tested for the abi lity of such cytokines to induce lytic viral reactivation in the latently i nfected BCBL-1 cell line. lnterferon-gamma consistently activated KSHV repl ication, whereas tumor necrosis factor, interleukin-1, interleukin-2, inter leukin-6, granulocyte-macrophage colony stimulating factor, and basic fibro blast growth factor did not. Glucocorticoids also failed to induce lytic KS HV growth in these cells, bur: ionomycin, a calcium ionophore, induced repl ication and strongly augmented the known inductive effects of phorbol ester s. Interferon-alpha had a dose-dependent inhibitory effect on KSHV inductio n by ionomycin. The identification of interferon-gamma as an activator and interferon-alpha as an inhibitor of KSHV induction in vitro correlates well with in vivo observations and demonstrates for the first time that inflamm atory cytokines can directly modulate KSHV replication. (C) 2000 Academic P ress.