Autocrine secretion of interferon-alpha/beta and tumour 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 (M phi). Infection of mouse M phi with HSV-2 results in an early (4 to 10 h) activation of the cells with an enhanced respiratory burst generated after membrane triggering with a phorbol ester. The role of monokines produced during this infection was analysed. Both interferon-alpha/beta (IFN-alpha/beta) and tumour necrosis factor-alpha (TNF-alpha) were produced within the very first hours after infection of M phi with HSV-2. Exogenously added IFN-alpha/beta conferred to M phi a respiratory burst capacity comparable to that seen after virus infection, whereas TNF-alpha by itself was unable to prime M phi for a respiratory burst. In fact concentrations of TNF-alpha comparable to those found in HSV-2-infected M phi cultures generally suppressed the response. However, when TNF-alpha was added together with IFN-alpha/beta a dose-dependent synergistic enhancement of the IFN-induced M phi activation was seen. The kinetics of the synergistic activation by the two monokines was similar to that seen with IFN-alpha/beta alone. Neutralizing antibodies to IFN-alpha/beta and TNF-alpha were able to diminish the HSV-induced priming of M phi for a respiratory burst. When the two antibodies were used together in subneutralizing concentrations an additional diminution of the responsiveness was seen, indicating that both monokines are involved in the virus-induced priming of M phi. However, high concentrations of antibodies to IFN-alpha/beta alone were able to abolish the activation completely, whereas this was not the case with anti-TNF-alpha. Collectively these data demonstrate that autocrine secretion of IFN-alpha/beta by M phi infected with HSV-2 is a sine qua non for the activation of M phi during the infection, and that this effect of IFN is synergistically enhanced, also in an autocrine manner, by TNF-alpha. It is suggested that this reciprocal M phi-monokine interaction may be of importance in resistance to virus infections.
Ellermann-Eriksen
S
S
Institute of Medical Microbiology, University of Aarhus, Denmark.
D000818:Animals; D016207:Cytokines / Q000378:metabolism / Q000502:physiology*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology; D016899:Interferon-beta / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016897:Respiratory Burst / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016207:Cytokines; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta