INTERLEUKIN-12 IS REQUIRED FOR INTERFERON-GAMMA PRODUCTION AND LETHALITY IN LIPOPOLYSACCHARIDE-INDUCED SHOCK IN MICE

Several cytokines, in particular tumor necrosis factor-alpha (TNF-alph a) and interferon-gamma (IFN-gamma), 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 endotoxin s (lipopolysaccharides, LPS). Priming of mice with the avirulent Bacil le Calmette Guerin (BCG) vaccine strain of Mycobacterium bovis increas es 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 mu g/mouse) of LPS, BCG-primed mice produce interleukin-12 (IL-12) which controls IFN-gamma production, as demonstrated by the ability o f neutralizing anti-IL-12 antibodies to suppress IFN-gamma production. However, the concentration of the biologically active IL-12 p70 heter odimer is similar in the serum of both BCG-primed or unprimed mice, re aching levels of 1-3 ng/ml at 3-6 h after LPS injection, whereas IFN-g amma production was observed only in BCG-primed mice. The priming effe ct of BCG on IFN-gamma production appears to be mostly due to its abil ity to increase TNF-alpha production, which acts as cofactor with LPS- induced IL-12 in inducing IFN-gamma production, as shown by the abilit y of injection of TNF-alpha and LPS (1 mu g/mouse), but not LPS alone, to induce IFN-gamma production, However, in addition to TNF-alpha, ot her LPS-induced cofactor(s) are required in cooperation with IL-12 to induce optimal IFN-gamma production, because co-injection of TNF-alpha and IL-12, sufficient to induce serum concentrations of both cytokine s higher and more persistent than those obtained by injection of LPS, was not sufficient to induce IFN-gamma production in vivo. Neutralizin g anti-IL-12 antibodies, in addition to inhibiting the in vivo LPS-ind uced IFN-gamma production, also completely protect BCG-primed mice inj ected with up to 10 mu g of LPS from shock-induced death. Thus, IL-12 is required for IFN-gamma production and lethality in an endotoxic sho ck model in mice.