Tsutsui H, Matsui K, Kawada N, Hyodo Y, Hayashi N, Okamura H, Higashino K, Nakanishi K
Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan.
J Immunol. 1997 Oct 15;159(8):3961-7.
When LPS is administered to heat-killed Propionibacterium acnes-primed BALB/c nude mice, they develop endotoxin-induced liver injury. As previously reported, this liver injury can be prevented by treatment with an Ab against IL-18, a novel cytokine with the ability to induce IFN-gamma production and up-regulate functional Fas ligand (FasL) expression. To identify the pathologic role of IL-18 in this liver injury, we investigated the hepatic cytokine network and FasL induction after LPS challenge. After LPS challenge to BALB/c nude mice, their livers expressed IL-12 mRNA, followed by the induction of IFN-gamma and FasL mRNA and then by the late elevation of TNF-alpha mRNA, but stably expressed IL-18 mRNA. The TNF-alpha induction curve had two peaks. The first peak was the result of the direct reaction to LPS, and the late peak might have been induced, since P. acnes-elicited Kupffer cells showed one-peak TNF-alpha kinetics in response to LPS stimulation in vitro. LPS-activated P. acnes-elicited Kupffer cells secreted both IL-12 and IL-18, as determined by ELISA and bioassay, respectively. The in vivo administration of anti-IL-18 just before an LPS challenge suppressed not only the induction of IFN-gamma and the late TNF-alpha elevation, but also the FasL induction, resulting in the total prevention of liver injury, whereas such an anti-IL-12 treatment did not. Anti-IFN-gamma treatment reduced the late increase in TNF-alpha, but not FasL, resulting in a partial prevention of the liver injury. The administration of anti-TNF-alpha just before elevation of the late TNF-alpha peak also markedly, but incompletely, suppressed the LPS-induced liver injury. These data suggested that IL-18 activates both TNF-alpha- and FasL-mediated hepatocytotoxic pathways in endotoxin-induced liver injury.
当将脂多糖（LPS）给予经热灭活的痤疮丙酸杆菌致敏的BALB/c裸鼠时，它们会发生内毒素诱导的肝损伤。如先前报道，这种肝损伤可通过用抗IL-18抗体治疗来预防，IL-18是一种新型细胞因子，具有诱导IFN-γ产生和上调功能性Fas配体（FasL）表达的能力。为了确定IL-18在这种肝损伤中的病理作用，我们研究了LPS攻击后肝脏细胞因子网络和FasL诱导情况。对BALB/c裸鼠进行LPS攻击后，其肝脏表达IL-12 mRNA，随后诱导IFN-γ和FasL mRNA，接着TNF-α mRNA出现后期升高，但稳定表达IL-18 mRNA。TNF-α诱导曲线有两个峰值。第一个峰值是对LPS直接反应的结果，后期峰值可能是由于痤疮丙酸杆菌引发的库普弗细胞在体外对LPS刺激显示出单峰TNF-α动力学而诱导产生的。通过ELISA和生物测定分别确定，LPS激活的痤疮丙酸杆菌引发的库普弗细胞分泌IL-12和IL-18。在LPS攻击前立即进行抗IL-18的体内给药不仅抑制了IFN-γ的诱导和TNF-α后期升高，还抑制了FasL诱导，从而完全预防了肝损伤，而这种抗IL-12治疗则没有效果。抗IFN-γ治疗减少了TNF-α后期升高，但未减少FasL，从而部分预防了肝损伤。在后期TNF-α峰值升高前立即给予抗TNF-α也显著但不完全抑制了LPS诱导的肝损伤。这些数据表明，在内毒素诱导的肝损伤中，IL-18激活了TNF-α和FasL介导的肝细胞毒性途径。
