A persistent immune response to herpes simplex virus type 1 (HSV-1) is evidenced by the expression of cytokine transcripts along with infiltrating mononuclear cells in the ganglia of latently infected mice. In trigeminal ganglion (TG) explant co-cultures, the presence of nonirradiated or irradiated primed splenocytes significantly reduced HSV-1 reactivation as defined by secreted infectious HSV-1 found in the supernatants of TG explant cultures. Primed splenocytes depleted of CD4+ or CD8+ cells did not antagonize HSV-1 reactivation. Cytokines including interleukin (IL)-2, IL-6, IL-10, and IL-12 were all detected in the TG explant cultures containing splenocytes. To further study the role of cytokines in HSV-1 reactivation, dissociated TG cell cultures were treated with exogenous recombinant cytokines including IFN-alpha or -gamma, IL-4, 6, 10, 12 or tumor necrosis factor (TNF)-alpha at concentrations ranging from 2.0 pg to 2.0 ng/culture (or 0.3-300 units/culture for the IFNs). While no cytokines tested at any concentration significantly modified HSV-1 reactivation, neutralizing antibody to IL-6, but not to IFN-alpha/beta, significantly antagonized HSV-1 reactivation. Collectively, the results suggest that IL-6 is directly or indirectly involved in HSV-1 reactivation in TG explant cultures.