Wysocka M, Kubin M, Vieira L Q, Ozmen L, Garotta G, Scott P, Trinchieri G
Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA.
Eur J Immunol. 1995 Mar;25(3):672-6. doi: 10.1002/eji.1830250307.
Several cytokines, in particular tumor necrosis factor-alpha (TNF-alpha) 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 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 microgram/mouse) of LPS, BCG-primed mice produce interleukin-12 (IL-12) which controls IFN-gamma production, as demonstrated by the ability of neutralizing anti-IL-12 antibodies to suppress IFN-gamma 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-gamma production was observed only in BCG-primed mice. The priming effect of BCG on IFN-gamma production appears to be mostly due to its ability to increase TNF-alpha production, which acts as cofactor with LPS-induced IL-12 in inducing IFN-gamma production, as shown by the ability of injection of TNF-alpha and LPS (1 microgram/mouse), but not LPS alone, to induce IFN-gamma production. However, in addition to TNF-alpha, other 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 cytokines higher and more persistent than those obtained by injection of LPS, was not sufficient to induce IFN-gamma production in vivo. Neutralizing anti-IL-12 antibodies, in addition to inhibiting the in vivo LPS-induced IFN-gamma production, also completely protect BCG-primed mice injected with up to 10 micrograms of LPS from shock-induced death. Thus, IL-12 is required for IFN-gamma production and lethality in an endotoxic shock model in mice.
几种细胞因子，特别是肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ），已被证明是导致病理反应的原因，这些病理反应可能导致在革兰氏阴性菌感染以及对内毒素（脂多糖，LPS）的反应中观察到的休克和死亡。用牛分枝杆菌无毒卡介苗（BCG）疫苗株对小鼠进行预刺激会增加小鼠对LPS致死效应的敏感性，并导致细胞因子产生的有效预刺激。响应低剂量（1微克/小鼠）的LPS，BCG预刺激的小鼠产生白细胞介素-12（IL-12），其控制IFN-γ的产生，这通过中和抗IL-12抗体抑制IFN-γ产生的能力得以证明。然而，BCG预刺激或未预刺激小鼠血清中生物活性IL-12 p70异二聚体的浓度相似，在LPS注射后3-6小时达到1-3 ng/ml的水平，而仅在BCG预刺激的小鼠中观察到IFN-γ的产生。BCG对IFN-γ产生的预刺激作用似乎主要归因于其增加TNF-α产生的能力，TNF-α与LPS诱导的IL-12共同作为诱导IFN-γ产生的辅助因子，这通过注射TNF-α和LPS（1微克/小鼠）而非单独注射LPS诱导IFN-γ产生的能力得以证明。然而，除了TNF-α之外，还需要其他LPS诱导的辅助因子与IL-12协同作用以诱导最佳的IFN-γ产生，因为共同注射TNF-α和IL-12，足以诱导血清中两种细胞因子的浓度高于并比注射LPS所获得的浓度更持久，但不足以在体内诱导IFN-γ产生。中和抗IL-12抗体，除了抑制体内LPS诱导的IFN-γ产生外，还能完全保护注射高达10微克LPS的BCG预刺激小鼠免于休克诱导的死亡。因此，在小鼠内毒素休克模型中，IFN-γ产生和致死性需要IL-12。
