The cooperative effects of TNF-a and IFN-’y are determining factors in the ability of IL-lO to protect mice from lethal endotoxemia

Recent studies have demonstrated that interleukin-lO (IL-b) has the capacity to protect mice from the lethal effects of endotoxin. In this investigation, we have examined the ability of IL-b to protect both normal mice and Corynebacterium parvum-primed mice against endotoxin lethality. In the overwhelming majority of experiments, recombinant murine IL-lO (rMuIL-1O) and recombinant human IL-lO (rHuIL-lO) did not protect normal BALB/cJ mice from lipopolysaccharide (LPS)-induced lethality at doses up to 10 pg/mouse. Despite their inability to protect, both IL-b preparations were highly effective in preventing the increase in serum tumor necrosis factor a (TNF-a) that occurred in response to the lethal dose of LPS. Moreover, a neutralizing antibody against TNF-a gave only partial protection when administered alone to BALB/cJ mice. Treatment with a combination of neutralizing antibodies against TNF-ct and interferon-’y (IFN-’y) resulted in complete protection. In contrast to BALB/cJ mice, normal BDF1 mice were protected from lethal endotoxemia by treatment with both rMuIL-10 and rHuIL-bO. However, IL-lO did not protect C. parvum-primed BDF1 against LPS lethality even though it caused a reduction in the LPS-induced serum TNF-a response in C. parvum-primed mice as well as in normal BDF1 mice. Neutralizing antibodies against TNF-a and IFN-’y were protective when administered alone to normal BDF1 mice, as previously demonstrated in C. parvum-primed mice. These findings suggest that lethal endotoxemia is a result of the cooperative activities of TNF-a and IFNy in normal mice of the BALB/CJ and BDF1 strains as well as in C. parvum-primed BDF1 mice. IL-tO appears to be less effective in protecting mice from lethal endotoxemia when cooperation between IFNy and TNF-a is facilitated by high-level production of the cytokines as in C. parvum-primed mice or when there is evidence of strong synergy between them as in normal BALB/cJ mice.J. Leukoc. Biol. 55: 711-718; 1994.