During a sublethal murine infection with Listerid monocytogenes cells, tumor necrosis factor (TNF) activity was detectable in neither sera nor spleen homogenates at any stage of the infection when a bioassay with L-929 cells (<4 U/ml) was used. However, injecting the mice with an immunoglobulin fraction obtained from a rabbit hyperimmunized with recombinant murine TNF-a resulted in acceleration of listeriosis. When 1 mg of anti-TNF antibody was injected per mouse, all the mice died from listeriosis, even though the infectious dose was sublethal for the untreated controls. The antigen-specific elimination of the bacterium from the spleens and livers of anti-TNF antibody-treated mice was delayed, depending on the dose of the antibody injected. Endogenous TNF seemed to be produced early in infection, because suppression of antiisterial resistance was significant when a single injection of anti-TNF antibody was given between day zero and day 2 of infection. The effect of endogenous TNF on antilisterial resistance was due to neither regulation of alpha interferon (IFN-a) * Corresponding author. ably due to the induction of both TNF receptor expression and the accumulation of mRNA for TNF by IFN-y (6, 35). Furthermore, the increased expression of major histocompatibility complex class I antigens by TNF is reported to be mediated by TNF-induced IFN-3 subtype 1 (IFN-fi1) or 0.01 M phosphate-buffered saline (PBS; pH 7.4).

Intravenous injection of rat anti-mouse gamma interferon (IFN--y) monoclonal antibody as well as rabbit anti-mouse tumor necrosis factor (TNF) antibody into mice which had received a sublethal infection with Listeria monocytogenes cells resulted in acceleration of listeriosis. Endogenous IFN-'y seemed to be produced early in infection, because suppression of antilisterial resistance was significant when a single injection of anti-IFN--y monoclonal antibody was given on day 0 or day 1 of infection. Production of TNF but not of IFN-y in the bloodstream early in infection was inhibited by administration of anti-IFN-y monoclonal antibody. The suppressive effect of anti-IFN-'y and anti-TNF antibodies on antilisterial resistance was not augmented by simultaneous administration of these antibodies. On the other hand, in the secondary infection, simultaneous administration of anti-IFN--y and anti-TNF antibodies, but not of either of these antibodies alone, into L. monocytogenes-immune mice resulted in high mortality and explosive multiplication of bacterial cells in the spleens and livers. These results suggest that endogenously produced IFN--y and TNF are both essential to the host defense against L. monocytogenes infection and that these cytokines might act by different modes between the primary infection and the secondary infection.

Mice were infected intravenously with a sublethal dose of Listeria monocytogenes cells and then levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), and gamma interferon (IFN-y) in the bloodstreams, spleens, and livers were monitored. The maximum level of TNF was detected at 72 h in the spleens and livers, but TNF was never detected in the bloodstreams. IL-6 appeared in the bloodstreams and spleens and peaked at 48 h. The maximum level of IFN-y could be detected in all three specimens, and the highest titer was shown in the spleens. Endogenous TNF production was suppressed by in vivo administration of anti-CD4 monoclonal antibody (MAb) or anti-asialo GM1 antibody but not by anti-CD8 MAb, whereas none of these antibodies suppressed endogenous IL-6 production. Endogenous production of neither IL-6 nor IFN-y was inhibited in rabbit antirecombinant mouse TNF-a antibody-treated mice. Similarly, production of TNF and IL-6 did not decrease in anti-mouse IFN-y MAb-treated animals, but TNF production was augmented in these animals. These results suggest that the these endogenous cytokines are produced by different mechanisms in L. monocytogenes infection. Complete elimination of Listeria monocytogenes, a facul-523 on July 16, 2020 by guest http://iai.asm.org/ Downloaded from INFECT. IMMUN. on July 16, 2020 by guest http://iai.asm.org/ Downloaded from

The production and roles of endogenous gamma interferon (IFN-␥), tumor necrosis factor (TNF), and interleukin-6 (IL-6) in both lethal and nonlethal infections of Staphylococcus aureus were investigated in mice. In the case of nonlethal infection, although no bacteria were detected in the bloodstreams, bacteria that colonized and proliferated persistently for 3 weeks were found in the kidneys. All mice given lethal injections died within 7 days, and large numbers of bacteria were detected in the bloodstreams, spleens, and kidneys. The first peaks of IFN-␥, TNF, and IL-6 were observed in the bloodstreams and spleens of the mice with nonlethal and lethal infections within 24 h. Thereafter, in the nonlethal cases, IFN-␥, TNF, and IL-6 peaked again in the spleens and kidneys during the period of maximum growth of bacteria in the kidneys, although only IL-6 was detected in the sera. In contrast, in the case of lethal infection, the titers of IFN-␥ and IL-6 in the sera and TNF in the kidneys peaked before death. Effects of in vivo administration of monoclonal antibodies (MAbs) against IFN-␥ and TNF on the fates of S. aureus-infected mice were studied. In the nonlethal infections, anti-TNF alpha (anti-TNF-␣) MAb-treated mice, but not anti-IFN-␥ MAb-treated mice, died as a result of worsening infection, suggesting that endogenous TNF plays a protective role in host resistance to S. aureus infection. In the mice that received lethal doses, injection of anti-TNF-␣ MAb accelerated death. However, although injection of anti-IFN-␥ MAb inhibited host resistance of the infected mice early in infection, most of the animals survived the lethal infection by injection of anti-IFN-␥ MAb, suggesting that endogenous IFN-␥ plays a detrimental role in S. aureus infection. Thus, this study demonstrated that IFN-␥ and TNF play different roles in S. aureus infection.

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