Lee Jie-Jen, Huang Wu-Tein, Shao Dong-Zi, Liao Jyh-Fei, Lin Mao-Tsun
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
Jpn J Physiol. 2003 Oct;53(5):367-75. doi: 10.2170/jjphysiol.53.367.
Lipopolysaccharide (LPS) stimulates peripheral mononuclear cells (PBMC) to synthesize or release pyrogenic cytokines, including interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha). Nuclear factor-kappa B (NF-kappaB) influences inflammatory responses through the regulation of genes encoding cytokines. In the present study, experiments were carried out to determine whether an inhibition of NF-kappaB mechanisms causes an inhibition of pyrogenic cytokine synthesis or release from PBMC and results in antipyresis. Intravenous administration of the supernatant fluids obtained from the human PBMC incubated with LPS caused feverlike hyperthermia in rabbits. The febrile responses were in parallel with the levels of IL-1beta, IL-6, and TNF-alpha in supernatant fluids. Both the fever and the increased levels of these cytokines in supernatant fluids were decreased by incubating LPS-PBMC with NF-kappaB inhibitors, including pyrrolidine dithiocarbamate, sodium pyrithione, N-acetyl-cysteine, and curcumin. Moreover, an intravenous administration of LPS (0.5-2 microg/kg) produced dose-dependent fever in the rabbits. The fevers were in parallel with the levels of IL-1beta, IL-6, and TNF-alpha in rabbit serum. A pretreatment of rabbits with an intravenous injection of pyrrolidine dithiocarbamate, sodium pryithione, N-acetyl-cysteine, or curcumin 1 h before the intravenous administration of LPS significantly attenuated the LPS-induced fever and/or increased levels of these cytokines in the serum of rabbits. Furthermore, pretreatment with an intravenous dose of anti-IL-1beta, anti-IL-6, or anti-TNF-alpha monoclonal antibody significantly attenuated the fever induced by the intravenous injection of LPS in rabbits. The antipyretic effects exerted by anti-L-1beta monoclonal antibody were greater than those exerted by anti-L-6 or anti-NF-alpha monoclonal antibody. The data indicate that NF-kappaB activation correlates with an LPS-induced synthesis or a release of cytokines (in particular, IL-1beta) from PBMC and triggers fever. Blocking NF-kappaB mechanisms in the PBMC with NF-kappaB inhibitors may be an effective strategy in the fever therapy.
脂多糖（LPS）刺激外周单核细胞（PBMC）合成或释放致热细胞因子，包括白细胞介素-1β（IL-1β）、IL-6和肿瘤坏死因子-α（TNF-α）。核因子-κB（NF-κB）通过调节细胞因子编码基因来影响炎症反应。在本研究中，进行实验以确定抑制NF-κB机制是否会抑制PBMC中致热细胞因子的合成或释放并导致退热。静脉注射从与LPS孵育的人PBMC中获得的上清液会使兔子出现类似发热的体温过高。发热反应与上清液中IL-1β、IL-6和TNF-α的水平平行。通过用NF-κB抑制剂（包括吡咯烷二硫代氨基甲酸盐、巯氧吡啶钠、N-乙酰半胱氨酸和姜黄素）孵育LPS-PBMC，可降低发热以及上清液中这些细胞因子的水平升高。此外，静脉注射LPS（0.5 - 2微克/千克）会使兔子产生剂量依赖性发热。发热与兔血清中IL-1β、IL-6和TNF-α的水平平行。在静脉注射LPS前1小时，用吡咯烷二硫代氨基甲酸盐、巯氧吡啶钠、N-乙酰半胱氨酸或姜黄素静脉注射预处理兔子，可显著减轻LPS诱导的发热和/或兔子血清中这些细胞因子水平的升高。此外，静脉注射抗IL-1β、抗IL-6或抗TNF-α单克隆抗体进行预处理可显著减轻静脉注射LPS诱导的兔子发热。抗IL-1β单克隆抗体发挥的退热作用大于抗IL-6或抗TNF-α单克隆抗体。数据表明，NF-κB激活与LPS诱导的PBMC中细胞因子（特别是IL-1β）的合成或释放相关，并引发发热。用NF-κB抑制剂阻断PBMC中的NF-κB机制可能是发热治疗中的一种有效策略。
