Flaviviruses comprise a positive-sense RNA genome that replicates exclusive
ly in the cytoplasm of infected cells. Whether flaviviruses require an acti
vated nuclear factor(s) to complete their life cycle and trigger apoptosis
in infected cells remains elusive. Flavivirus infections quickly activate n
uclear factor kappa B (NF-kappaB), and salicylates have been shown to inhib
it NF-kappaB activation. In this study, we investigated whether salicylates
suppress flavivirus replication and virus-induced apoptosis in cultured ce
lls. In a dose-dependent inhibition, we found salicylates within a range of
1 to 5 mM not only restricted flavivirus replication but also abrogated fl
avivirus-triggered apoptosis. However, flavivirus replication was not affec
ted by a specific NF-kappaB peptide inhibitor, SN50, and a proteosome inhib
itor, lactacystin. Flaviviruses also replicated and triggered apoptosis in
cells stably expressing I kappaB alpha-DeltaN, a dominant-negative mutant t
hat antagonizes NF-kappaB activation, as readily as in wild-type BHK-21 cel
ls, suggesting that NF-kappaB activation is not essential for either flaviv
irus replication or flavivirus-induced apoptosis. Salicylates still diminis
hed flavivirus replication and blocked apoptosis in the same I kappaB alpha
-DeltaN cells. This inhibition of flaviviruses by salicylates could be part
ially reversed by a specific p38 mitogen-activated protein (MAP) kinase inh
ibitor, SB203580. Together, these results show that the mechanism by which
salicylates suppress flavivirus infection may involve p38 MAP kinase activi
ty but is independent of blocking the NF-kappaB pathway.