Jansen P M, de Jong I W, Hart M, Kim K J, Aarden L A, Hinshaw L B, Taylor F B, Hack C E
Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Clinical and Experimental Immunology, University of Amsterdam, The Netherlands.
J Immunol. 1996 Jun 1;156(11):4401-7.
Leukemia inhibitory factor (LIF), a pleiotropic cytokine with many biologic effects overlapping with those of IL-6, has been implicated in the pathogenesis of sepsis. We here analyzed the kinetics of LIF in 13 baboons challenged with a lethal (n=6) or sublethal (n=7) dose of Escherichia coli. In addition, to assess the role of TNF-alpha in the induction of LIF in vivo, seven baboons were studied that had either received a bolus injection of recombinant human TNF-alpha (100 micrograms/kg, n=3), or to whom 15 mg/kg of an anti-TNF mAB before lethal E. coli challenge was administered (n=4). LIF levels increased 2 h after E coli challenge, and reached maximum values at 4 and 8 h after a sublethal (4.4 +/- 1.6 ng/ml) or lethal (40.9 +/- 3.8 ng/ml) dose, respectively. TNF-alpha injection induced a modest rise in LIF concentrations, peaking after 6 h (228 +/- 46 pg/ml). Circulating LIF correlated with plasma levels of IL-6, both after E. coli challenge (Spearman Rank coefficient of correlation (r) = 0.849, p<0.001), as well as upon TNF-alpha injection (r=0.863, p<0.001). Moreover, the E. coli-induced release of either cytokine was reduced 6- to 10-fold after pretreatment with anti-TNF mAb, except in one nonsurviving animal, which exhibited a progressive increase of LIF and IL-6 levels despite the absence of TNF immunoreactivity. These results show that TNF-alpha is an intermediate factor in concerted release of LIF and IL-6 in vivo, and indicate that the enhanced elaboration of these cytokines may predict disease outcome in severe sepsis.
白血病抑制因子（LIF）是一种多效性细胞因子，具有许多与白细胞介素-6重叠的生物学效应，已被认为与脓毒症的发病机制有关。我们在此分析了13只接受致死剂量（n = 6）或亚致死剂量（n = 7）大肠杆菌攻击的狒狒体内LIF的动力学。此外，为了评估肿瘤坏死因子-α（TNF-α）在体内诱导LIF中的作用，研究了7只狒狒，其中3只接受了重组人TNF-α的大剂量注射（100微克/千克），另外4只在接受致死剂量大肠杆菌攻击前给予了15毫克/千克的抗TNF单克隆抗体（mAB）。大肠杆菌攻击后2小时LIF水平升高，在亚致死剂量（4.4±1.6纳克/毫升）或致死剂量（40.9±3.8纳克/毫升）攻击后分别在4小时和8小时达到最大值。注射TNF-α导致LIF浓度适度升高，6小时后达到峰值（228±46皮克/毫升）。大肠杆菌攻击后以及注射TNF-α后，循环LIF均与白细胞介素-6的血浆水平相关（Spearman等级相关系数（r）分别为0.849，p<0.001和r = 0.863，p<0.001）。此外，除了一只未存活的动物外，用抗TNF mAb预处理后，大肠杆菌诱导的两种细胞因子的释放均减少了6至10倍，该未存活动物尽管没有TNF免疫反应性，但LIF和白细胞介素-6水平却持续升高。这些结果表明，TNF-α是体内LIF和白细胞介素-6协同释放的中间因子，并表明这些细胞因子的过度分泌可能预示着严重脓毒症的疾病结局。
