Tiegs G, Barsig J, Matiba B, Uhlig S, Wendel A
Department of Biochemical Pharmacology, Faculty of Biology, University of Konstanz, Germany.
J Clin Invest. 1994 Jun;93(6):2616-22. doi: 10.1172/JCI117274.
GM-CSF is known to prime leukocytes for inflammatory stimuli in vitro. The objective of this study was to investigate the role of GM-CSF in vivo in a systemic inflammatory reaction syndrome. The results demonstrate a potentiation of LPS toxicity by GM-CSF in a mortality model as well as in a septic liver failure model in mice. Pretreatment of animals with 50 micrograms/kg GM-CSF induced lethality within 24 h in mice challenged with a subtoxic dose of LPS while controls survived > 72 h. A monoclonal anti-GM-CSF antibody significantly protected against a lethal LPS dose. Serum GM-CSF was inducible by LPS and peaked at 2 h. GM-CSF pretreatment dramatically potentiated systemic TNF release and hepatotoxicity induced by a subtoxic dose of LPS in galactosamine-sensitized mice. Potentiation of LPS hepatotoxicity was possible until 30 min after LPS challenge. Polyclonal anti-GM-CSF IgG protected against septic liver failure in this model and attenuated serum TNF concentrations. In vitro an ex vivo experiments revealed that after GM-CSF pretreatment LPS-induced IL-1 release from bone marrow or spleen cells was also enhanced. These findings suggest that GM-CSF represents an endogenous enhancer of LPS-induced organ injury, possibly by potentiating the release of proinflammatory cytokines such as TNF and IL-1.
已知粒细胞-巨噬细胞集落刺激因子（GM-CSF）可在体外使白细胞对炎症刺激产生预激活作用。本研究的目的是探讨GM-CSF在全身炎症反应综合征体内过程中的作用。结果表明，在小鼠的死亡率模型以及脓毒症肝衰竭模型中，GM-CSF可增强脂多糖（LPS）的毒性。用50微克/千克GM-CSF对动物进行预处理，可使接受亚毒性剂量LPS攻击的小鼠在24小时内死亡，而对照组存活时间超过72小时。一种抗GM-CSF单克隆抗体可显著保护动物免受致死剂量LPS的攻击。LPS可诱导血清GM-CSF升高，并在2小时达到峰值。GM-CSF预处理可显著增强半乳糖胺致敏小鼠经亚毒性剂量LPS诱导的全身肿瘤坏死因子（TNF）释放及肝毒性。LPS攻击后30分钟内，LPS肝毒性增强效应仍存在。在此模型中，多克隆抗GM-CSF IgG可预防脓毒症肝衰竭，并降低血清TNF浓度。体外及离体实验表明，GM-CSF预处理后，LPS诱导骨髓或脾细胞释放白细胞介素-1（IL-1）也增强。这些发现提示，GM-CSF可能通过增强TNF和IL-1等促炎细胞因子的释放，成为LPS诱导器官损伤的内源性增强因子。
