Marchant A, Bruyns C, Vandenabeele P, Ducarme M, Gérard C, Delvaux A, De Groote D, Abramowicz D, Velu T, Goldman M
Hôpital Erasme-Department of Immunology, Brussels, Belgium.
Eur J Immunol. 1994 May;24(5):1167-71. doi: 10.1002/eji.1830240524.
Interleukin-10 (IL-10) is a potent inhibitor of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production and has been shown to protect mice from endotoxin shock. As IFN-gamma is another important mediator of LPS toxicity, we studied the effects of IL-10 on LPS-induced IFN-gamma synthesis in vitro and in vivo. First, we found that the addition of recombinant human IL-10 (rhIL-10) (10 U/ml) to human whole blood markedly suppressed LPS-induced IFN-gamma release while neutralization of endogenously synthesized IL-10 resulted in increased IFN-gamma levels. The ability of rIL-10 to inhibit LPS-induced IFN-gamma synthesis was also observed in vivo in mice. Indeed, administration of 1000 U recombinant mouse IL-10 (rmIL-10) 30 min before and 3 h after challenge of BALB/c mice with 100 micrograms LPS resulted in a threefold decrease in peak IFN-gamma serum levels. We then examined the production and the role of IL-10 during murine endotoxemia. We found that LPS injection causes the rapid release of IL-10, peak IL-10 serum levels being observed 90 min after LPS challenge. Neutralization of endogenously produced IL-10 by administration of 2 mg JES5-2A5 anti-IL-10 monoclonal antibody (mAb) 2 h before LPS challenge resulted in a marked increase in both TNF and IFN-gamma serum levels while irrelevant isotype-matched mAb had no effect. The enhanced production of inflammatory cytokines in anti-IL-10 mAb-treated mice was associated with a 60% lethality after injection of 500 micrograms LPS, while all mice pretreated with control mAb survived. We conclude that the rapid release of IL-10 during endotoxemia is a natural antiinflammatory response controlling cytokine production and LPS toxicity.
白细胞介素-10（IL-10）是脂多糖（LPS）诱导的肿瘤坏死因子（TNF）产生的有效抑制剂，已证明其可保护小鼠免受内毒素休克。由于干扰素-γ（IFN-γ）是LPS毒性的另一个重要介质，我们研究了IL-10在体外和体内对LPS诱导的IFN-γ合成的影响。首先，我们发现向人全血中添加重组人IL-10（rhIL-10）（10 U/ml）可显著抑制LPS诱导的IFN-γ释放，而中和内源性合成的IL-10则导致IFN-γ水平升高。在小鼠体内也观察到rIL-10抑制LPS诱导的IFN-γ合成的能力。实际上，在用100微克LPS攻击BALB/c小鼠前30分钟和攻击后3小时给予1000 U重组小鼠IL-10（rmIL-10），可使血清IFN-γ峰值水平降低三倍。然后，我们研究了IL-10在小鼠内毒素血症期间的产生及其作用。我们发现注射LPS会导致IL-10迅速释放，在LPS攻击后90分钟观察到血清IL-10峰值水平。在LPS攻击前2小时给予2毫克JES5-2A5抗IL-10单克隆抗体（mAb）中和内源性产生的IL-10，可导致TNF和IFN-γ血清水平显著升高，而无关的同型匹配mAb则无作用。在用抗IL-10 mAb处理的小鼠中，炎性细胞因子产生的增加与注射500微克LPS后60%的致死率相关，而所有用对照mAb预处理的小鼠均存活。我们得出结论，内毒素血症期间IL-10的迅速释放是一种控制细胞因子产生和LPS毒性的天然抗炎反应。
