Brouckaert P, Everaerdt B, Fiers W
Laboratory of Molecular Biology, State University, Gent, Belgium.
Eur J Immunol. 1992 Apr;22(4):981-6. doi: 10.1002/eji.1830220416.
Although tumor necrosis factor (TNF) is undoubtedly a major mediator of the antitumor and shock-inducing activities of lipopolysaccharide (LPS), the outcome of a challenge with TNF is highly dependent on the presence or absence of other substances or conditions. We have previously shown that to obtain lethality in mice after TNF administration both TNF receptor (TNF-R) types have to be triggered. This is illustrated by the fact that recombinant human (rh) TNF, which is a selective murine (m) TNF-R55 agonist, is not lethal, whereas mTNF, which binds both mTNF-R55 and mTNF-R75, is lethal in mice. Triggering of TNF-R75 is, however, no longer needed when sensitizers such as galactosamine or low doses of LPS or interleukin (IL)-1 are also present. Here, we report that this selective species specificity of TNF is also reflected in patterns of induced IL-6: both rmTNF and rhTNF could induce considerable IL-6 peak levels in the plasma (up to 10 ng/ml) 2 to 3 h after TNF administration. However, only rmTNF was capable of inducing the same pattern of sustained IL-6 levels previously observed after lethal LPS doses, while rhTNF only caused induction of transient IL-6 levels, as found after nonlethal LPS doses. We also observed that the sensitizer IL-1 could complement rhTNF to induce such a sustained IL-6 induction. Since we were interested in sensitizers with a defined mechanism of action, we further investigated the effects of the glucocorticoid and progesterone inhibitor RU38486 on the lethal and IL-6-inducing properties of TNF. We observed that RU38486 closely mimicked IL-1: both had similar effects on IL-6 induction and sensitized mice to the lethal effects of TNF with comparable efficiency and kinetics. Using a monoclonal anti-IL-1R antibody, we finally observed that the effects of RU38486 were most probably not mediated by IL-1. These observations suggest that a glucocorticoid-antagonistic activity might be a key factor in the pathways leading to septic shock and that such activity could be a key target for the pharmacological manipulation of sepsis.
尽管肿瘤坏死因子（TNF）无疑是脂多糖（LPS）抗肿瘤和诱导休克活性的主要介质，但TNF攻击的结果高度依赖于其他物质或条件的存在与否。我们之前已经表明，要在给小鼠注射TNF后使其致死，必须触发两种TNF受体（TNF-R）类型。这一点可通过以下事实说明：重组人（rh）TNF是一种选择性鼠（m）TNF-R55激动剂，不具有致死性，而能同时结合mTNF-R55和mTNF-R75的mTNF在小鼠中具有致死性。然而，当存在半乳糖胺或低剂量LPS或白细胞介素（IL）-1等致敏剂时，触发TNF-R75就不再必要。在此，我们报告TNF的这种选择性物种特异性也反映在诱导的IL-6模式中：在注射TNF后2至3小时，rmTNF和rhTNF均可在血浆中诱导出相当高的IL-6峰值水平（高达10 ng/ml）。然而，只有rmTNF能够诱导出与致死剂量LPS后先前观察到的相同的持续IL-6水平模式，而rhTNF仅引起短暂的IL-6水平诱导，这与非致死剂量LPS后的情况相同。我们还观察到致敏剂IL-1可以补充rhTNF以诱导这种持续的IL-6诱导。由于我们对具有明确作用机制的致敏剂感兴趣，我们进一步研究了糖皮质激素和孕酮抑制剂RU38486对TNF致死性和诱导IL-6特性的影响。我们观察到RU38486与IL-1非常相似：两者对IL-6诱导具有相似的作用，并以相当的效率和动力学使小鼠对TNF的致死作用敏感。使用单克隆抗IL-1R抗体，我们最终观察到RU38486的作用很可能不是由IL-1介导的。这些观察结果表明，糖皮质激素拮抗活性可能是导致脓毒症休克途径中的关键因素，并且这种活性可能是脓毒症药理调控的关键靶点。
