Interleukin‐12 is required for interferon‐γ production and lethality in lipopolysaccharide‐induced shock in mice

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Abstract
Several cytokines, in particular tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ), have been shown to be responsible for pathological reactions which may lead to shock and death observed in infection with Gram‐negative bacteria and in response to endotoxins (lipopolysaccharides, LPS). Priming of mice with the avirulent Bacille Calmette Guérin (BCG) vaccine strain of Mycobacterium bovis increases the sensitivity of mice to the lethal effect of LPS and results in an efficient priming for cytokine production. In response to low doses (1 γg/mouse) of LPS, BCG‐primed mice produce interleukin‐12 (IL‐12) which controls IFN‐γ production, as demonstrated by the ability of neutralizing anti‐IL‐12 antibodies to suppress IFN‐γ production. However, the concentration of the biologically active IL‐12 p70 heterodimer is similar in the serum of both BCG‐primed or unprimed mice, reaching levels of 1–3 ng/ml at 3–6 h after LPS injection, whereas IFN‐γ production was observed only in BCG‐primed mice. The priming effect of BCG on IFN‐γ production appears to be mostly due to its ability to increase TNF‐α production, which acts as cofactor with LPS‐induced IL‐12 in inducing IFN‐γ production, as shown by the ability of injection of TNF‐α and LPS (1 γg/mouse), but not LPS alone, to induce IFN‐γ production. However, in addition to TNF‐α, other LPS‐induced cofactor(s) are required in cooperation with IL‐12 to induce optimal IFN‐γ production, because co‐injection of TNF‐α and IL‐12, sufficient to induce serum concentrations of both cytokines higher and more persistent than those obtained by injection of LPS, was not sufficient to induce IFN‐γ production in vivo. Neutralizing anti‐IL‐12 antibodies, in addition to inhibiting the in vivo LPS‐induced IFN‐γ production, also completely protect BCG‐primed mice injected with up to 10 μg of LPS from shock‐induced death. Thus, IL‐12 is required for IFN‐γ production and lethality in an endotoxic shock model in mice.