AUTOCRINE SECRETION OF INTERFERON-ALPHA BETA AND TUMOR-NECROSIS-FACTOR-ALPHA SYNERGISTICALLY ACTIVATES MOUSE MACROPHAGES AFTER INFECTION WITH HERPES-SIMPLEX VIRUS TYPE-2/

Resistance of mice to infection with herpes simplex virus type 2 (HSV- 2) is strongly dependent on the function of macrophages (Mphi). Infect ion of mouse Mphi with HSV-2 results in an early (4 to 10 h) activatio n of the cells with an enhanced respiratory burst generated after memb rane triggering with a phorbol ester. The role of monokines produced d uring this infection was analysed. Both interferon-alpha/beta (IFN-alp ha/beta) and tumour necrosis factor-alpha (TNF-alpha) were produced wi thin the very first hours after infection of Mphi with HSV-2. Exogenou sly added IFN-alpha/beta conferred to Mphi a respiratory burst capacit y comparable to that seen after virus infection, whereas TNF-alpha by itself was unable to prime Mphi for a respiratory burst. In fact conce ntrations of TNF-alpha comparable to those found in HSV-2-infected Mph i cultures generally suppressed the response. However, when TNF-alpha was added together with IFN-alpha/beta a dose-dependent synergistic en hancement of the IFN-induced Mphi activation was seen. The kinetics of the synergistic activation by the two monokines was similar to that s een with IFN-alpha/beta alone. Neutralizing antibodies to IFN-alpha/be ta and TNF-alpha were able to diminish the HSV-induced priming of Mphi for a respiratory burst. When the two antibodies were used together i n subneutralizing concentrations an additional diminution of the respo nsiveness was seen, indicating that both monokines are involved in the virus-induced priming of Mphi. However, high concentrations of antibo dies to IFN-alpha/beta alone were able to abolish the activation compl etely, whereas this was not the case with anti-TNF-alpha. Collectively these data demonstrate that autocrine secretion of IFN-alpha/beta by Mphi infected with HSV-2 is a sine qua non for the activation of Mphi during the infection, and that this effect of IFN is synergistically e nhanced, also in an autocrine manner, by TNF-alpha. It is suggested th at this reciprocal Mphi-monokine interaction may be of importance in r esistance to virus infections.