HERPES-SIMPLEX VIRUS TYPE-2 SYNERGIZES WITH INTERFERON-GAMMA IN THE INDUCTION OF NITRIC-OXIDE PRODUCTION IN MOUSE MACROPHAGES THROUGH AUTOCRINE SECRETION OF TUMOR-NECROSIS-FACTOR-ALPHA

We have analysed the ability of herpes simplex virus type 2 (HSV-2) to induce nitric oxide (NO) production in resting BALB/c mouse peritonea l macrophages. In most experiments, macrophages produced very small am ounts of NO upon infection with HSV-2. Mock virus preparations did not induce NO production, and virus inactivation experiments showed that infectious virus was required, Since interferon-gamma (IFN-gamma) is t he prototype cytokine that is able to induce significant NO production in macrophages, we found it of interest to examine the influence of H SV-2 infection on the IFN-gamma-induced NO production, The virus exert ed a synergistic effect on the IFN-gamma-induced NO release, which was accompanied by induction of the iNOS-gene as revealed by RT-PCR. This effect was largely dependent on the presence of infectious virus part icles, since only a minor effect was seen with mock virus and inactiva ted virus preparations, From experiments with neutralizing antibodies to tumour necrosis factor-alpha (TNF-alpha) and IFN-alpha/beta it was concluded that the synergistic effect is dependent on autocrine secret ion of TNF-alpha, which acts as a second signal and synergizes with IF N-gamma in NO production.