Dharmana Edi, Keuter Monique, Netea Mihai G, Verschueren Ineke C M M, Kullberg Bart Jan
Department of Parasitology, Faculty of Medicine, Diponegoro University, Semarang, Indonesia.
Eur Cytokine Netw. 2002 Jan-Mar;13(1):104-9.
During septic shock with Gram-negative microorganisms, mortality is determined by two independent factors: high concentrations of circulating proinflammatory cytokines and multiplication of the microorganisms in the organs of the host. We studied the role of endogenous tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha (LT) in the pathogenesis of lethal endotoxemia and infection with viable Salmonella typhimurium. Compared to wild-type control mice, TNF-/-LT-/- knock-out mice were more resistant (100% versus 25% mortality) to a lethal challenge with LPS, due to a significantly decreased production of the proinflammatory cytokines TNF, IL-1alpha and IL-1beta. In contrast, TNF-/-LT-/- mice were highly susceptible to infection with viable S. typhimurium as compared to wild-type mice (100% versus 0% mortality), and this was accompanied by a 100-fold greater bacterial load in their organs. The effect of endogenous TNF and LT during infection was mediated by a defective recruitment of neutrophils at the site of infection, as well as a reduced intracellular killing of S. typhimurium by these cells. These results show that TNF and LT have crucial, yet opposite effects on lethal endotoxemia induced by S. typhimurium LPS and on the infection of mice with live Salmonella microorganisms, and suggest caution when extrapolating results obtained in the lethal endotoxemia model to bacteremia in patients.
在革兰氏阴性微生物引起的脓毒性休克中，死亡率由两个独立因素决定：循环中促炎细胞因子的高浓度以及微生物在宿主器官中的增殖。我们研究了内源性肿瘤坏死因子-α（TNF）和淋巴毒素-α（LT）在致死性内毒素血症和鼠伤寒沙门氏菌活菌感染发病机制中的作用。与野生型对照小鼠相比，TNF-/-LT-/-基因敲除小鼠对LPS致死性攻击更具抵抗力（死亡率分别为100%和25%），这是因为促炎细胞因子TNF、IL-1α和IL-1β的产生显著减少。相反，与野生型小鼠相比，TNF-/-LT-/-小鼠对鼠伤寒沙门氏菌活菌感染高度敏感（死亡率分别为100%和0%），并且其器官中的细菌载量高100倍。感染期间内源性TNF和LT的作用是由感染部位中性粒细胞募集缺陷以及这些细胞对鼠伤寒沙门氏菌的细胞内杀伤减少介导的。这些结果表明，TNF和LT对鼠伤寒沙门氏菌LPS诱导的致死性内毒素血症以及小鼠感染活沙门氏菌微生物具有关键但相反的作用，并提示在将致死性内毒素血症模型中获得的结果外推至患者菌血症时需谨慎。
