Randow F, Döcke W D, Bundschuh D S, Hartung T, Wendel A, Volk H D
Institute of Medical Immunology, Charité Medical School, Humboldt-University Berlin, Germany.
J Immunol. 1997 Mar 15;158(6):2911-8.
LPS tolerance is characterized by a diminished monocytic synthesis of TNF-alpha and, interestingly, IL-10 after LPS restimulation. We wondered whether granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, and IFN-gamma can prevent or reverse this down-regulation of TNF-alpha and IL-10 production. The LPS-induced TNF-alpha amounts in desensitized PBMC treated with GM-CSF, IFN-gamma, or IL-12 and in naive, non-cytokine-primed cultures were similar, while much more TNF-alpha was induced in cytokine-primed naive cells. The effect of IL-12 was dependent on the presence of nonmonocytic cells and could be completely blocked with an IFN-gamma antiserum. Treatment of LPS-desensitized pure monocytes with IFN-gamma or GM-CSF resulted in a very high TNF-alpha expression and no difference to cytokine-primed naive monocytes was evident any longer. While IFN-gamma and IL-12 decreased IL-10 expression in naive PBMC, it was increased by both and by GM-CSF in LPS-tolerant cultures. Again, only IL-12 was dependent on the presence of nonmonocytic cells. For prevention of LPS tolerance, similar results were obtained. Recently, we have shown that IL-10 and TGF-beta mediate LPS desensitization in vitro and can be used to establish LPS hyporesponsiveness in the absence of LPS. IFN-gamma and GM-CSF prevented and reversed down-regulation of TNF-alpha and IL-10 synthesis also in the model of IL-10/TGF-beta1-induced LPS hyporesponsiveness, while IL-12 was ineffective because of its obvious inability to induce IFN-gamma. In summary, after LPS desensitization/hyporesponsiveness, IFN-gamma and GM-CSF tended to normalize pro- and anti-inflammatory monocytic behavior. Our results suggest that during LPS desensitization/hyporesponsiveness, monocytes acquire a hitherto unknown functional state with an altered reaction to biologic response modifiers.
脂多糖（LPS）耐受的特征是脂多糖再次刺激后单核细胞合成肿瘤坏死因子-α（TNF-α）减少，有趣的是，白细胞介素-10（IL-10）也减少。我们想知道粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IL-12和干扰素-γ（IFN-γ）是否能预防或逆转TNF-α和IL-10产生的这种下调。在用GM-CSF、IFN-γ或IL-12处理的脱敏外周血单核细胞（PBMC）以及未用细胞因子预刺激的原始培养物中，LPS诱导的TNF-α量相似，而在细胞因子预刺激的原始细胞中诱导的TNF-α要多得多。IL-12的作用取决于非单核细胞的存在，并且可以被IFN-γ抗血清完全阻断。用IFN-γ或GM-CSF处理LPS脱敏的纯单核细胞导致非常高的TNF-α表达，并且与细胞因子预刺激的原始单核细胞不再有明显差异。虽然IFN-γ和IL-12降低了原始PBMC中IL-10的表达，但在LPS耐受培养物中，两者以及GM-CSF都使其升高。同样，只有IL-12的作用取决于非单核细胞的存在。对于LPS耐受的预防，也获得了类似的结果。最近，我们已经表明IL-10和转化生长因子-β（TGF-β）在体外介导LPS脱敏，并且可以用于在没有LPS的情况下建立LPS低反应性。在IL-10/TGF-β1诱导的LPS低反应性模型中，IFN-γ和GM-CSF也预防并逆转了TNF-α和IL-10合成的下调，而IL-12无效，因为它明显无法诱导IFN-γ。总之，在LPS脱敏/低反应性后，IFN-γ和GM-CSF倾向于使促炎和抗炎单核细胞行为正常化。我们的结果表明，在LPS脱敏/低反应性期间，单核细胞获得了一种迄今未知的功能状态，对生物反应调节剂的反应发生了改变。
