Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E-coli challenge
Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E-coli challenge
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DOI：
10.1152/japplphysiol.00371.2003
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发表时间：
2003-11-01
影响因子：
3.3
通讯作者：
Fleshner, M
中科院分区：
文献类型：
--
作者：
Campisi, J;Hansen, MK;Fleshner, M
外周给予各种炎症刺激物，如内毒素或细胞因子，诱导一系列脑介导的事件，称为疾病反应。免疫产物如何向大脑发出信号的机制尚不清楚，但越来越多的证据支持神经和血液传播途径的存在。虽然内毒素或细胞因子的施用导致疾病反应，但关于循环内毒素或细胞因子在真实的细菌感染期间诱导疾病中的作用的数据很少。因此，目前的研究检查是否皮下注射大肠杆菌可以激活疾病的反应，是否循环内毒素和/或促炎细胞因子是这些反应的先决条件。雄性Sprague-Dawley大鼠皮下注射三种剂量（2.5 × 10（7），2.5 × 10（8），2.5 × 10（9）菌落形成单位）的复制型E。大肠杆菌、普遍存在的细菌菌株或载体。注射后3天测量核心体温（T-c）和活动。在注射后3、6、12、18、24和48 h处死第二组动物，并采集血样和脑组织。注射剂量依赖性和一致性增加T-c和降低活动，与T-c增加开始注射后4小时。此外，E.从6 h时间点开始，大肠杆菌显著增加血清白细胞介素（IL）-1 β、IL-6和肿瘤坏死因子-α以及脑IL-1 β水平。皮质酮和内毒素分别在注射后3小时和18小时首先在循环中升高。由于发热发生在脑细胞因子诱导之前，我们还检查了注射后2小时和4小时血清、脑和炎症部位中的细胞因子水平。细胞因子在炎症部位升高，但在2和4 h的血清或脑中未检测到。我们的结论是，皮下注射复制E。大肠杆菌引起一致的和自然的感染，包括疾病反应的特征以及循环、脑和炎症部位组织细胞因子的增加。此外，注射复制型E.大肠杆菌在循环细胞因子或内毒素没有可检测到的增加时产生强烈的发热和皮质酮反应。这些结果表明，循环细胞因子和内毒素水平的升高是不必要的疾病或皮质酮反应的激活。因此，E.大肠杆菌感染可能是由神经而非体液途径从外周到大脑诱发的。
Peripheral administration of a variety of inflammatory stimuli, such as endotoxin or cytokines, induces an orchestrated set of brain-mediated events referred to as the sickness response. The mechanism for how immune products signal the brain is not clear, but accumulating evidence supports the existence of neural as well as blood-borne pathways. Although endotoxin or cytokine administration results in sickness responses, few data exist regarding the role of circulating endotoxin or cytokines in the induction of sickness during a real bacterial infection. Thus the present studies examined whether subcutaneously administered Escherichia coli can activate sickness responses and whether circulating endotoxin and/or proinflammatory cytokines are a prerequisite for these responses. Male Sprague-Dawley rats were injected subcutaneously with one of three doses (2.5 x 10(7), 2.5 x 10(8), 2.5 x 10(9) colony-forming units) of replicating E. coli, a ubiquitous bacterial strain, or vehicle. Core body temperature (T-c) and activity were measured for 3 days after the injection. A second set of groups of animals were killed 3, 6, 12, 18, 24, and 48 h after the injection, and blood samples and brains were collected. Injections dose dependently and consistently increased T-c and decreased activity, with increases in T-c beginning 4 h after the injection. In addition, E. coli significantly increased serum interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha and brain IL-1beta levels beginning at the 6-h time point. Corticosterone and endotoxin were first elevated in the circulation at 3 and 18 h after the injection, respectively. Because fever onset preceded brain cytokine induction, we also examined cytokine levels in the serum, brain, and inflammation site 2 and 4 h after injection. Cytokines were elevated at the inflammation site but were not detectable in the serum or brain at 2 and 4 h. We conclude that subcutaneous injection of replicating E. coli induces a consistent and naturalistic infection that includes features of the sickness response as well as increases in circulating, brain, and inflammation site tissue cytokines. In addition, injection of replicating E. coli produces a robust fever and corticosterone response at a time when there are no detectable increases in circulating cytokines or endotoxin. These results suggest that elevated levels of circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response. Therefore, fever, activity reduction, and corticosterone elevation induced by E. coli infection may have been evoked by a neural, rather than a humoral, pathway from the periphery to the brain.