Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain
Activation of the inflammatory transcription factor nuclear factor interleukin-6 during inflammatory and psychological stress in the brain
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DOI：
10.1186/1742-2094-10-140
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发表时间：
2013-11-26
影响因子：
9.3
通讯作者：
Rummel, Christoph
中科院分区：
文献类型：
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作者：
Fuchs, Franziska;Damm, Jelena;Rummel, Christoph
背景：转录因子核因子-白介素6(NF-IL6)被脑内各种炎症刺激所激活。有趣的是，我们最近检测到系统注射脂多糖后大鼠下丘脑-垂体-肾上腺(HPA)轴中的NF-IL-6激活。因此，本研究的目的是探讨在炎症性或心理应激状态下，大鼠脑组织中的核因子-IL-6是否被激活。或者暴露在新奇的环境中。遥测核心体温(TB)和运动活动，不同时间点处死动物，取脑和血，进行脑垂体前叶(AL)原代细胞培养。结果：一种新环境的应激刺激增加了垂体血管周围巨噬细胞和下丘脑室旁细胞的NF-IL6免疫反应活性(IR)，TB增加，持续约2小时。在体内和体外，LPS刺激导致包括ACTH-IR阳性的皮质细胞在内的其他几种细胞的NF-IL6-IR。另外两种促炎转录因子信号转导和转录激活因子(STAT)3和核因子kappaB仅在内毒素刺激后才在AL细胞中被显著激活，并与NF-IL6-IR部分共存，而在心理应激后则不能。在体外，核因子-IL-6的激活与卵泡星状细胞中肿瘤坏死因子α的诱导和分泌有关，这种作用可被JAK-STAT抑制剂AG490拮抗。结论：首次揭示了核因子-IL-6的激活不仅发生在炎症性脂多糖刺激过程中，而且还发生在心理应激过程中，即一个新的环境。这两种应激源都与脑组织和脑垂体不同细胞类型中NF-IL6的时间依赖性激活有关。此外，虽然NF-IL6-IR与脂多糖刺激后STAT3和NF-kappa B的激活、肿瘤坏死因子α的产生和ACTH-IR部分相关，但在暴露于新环境后情况并非如此，这表明了不同的潜在信号通路。总体而言，在大脑中，核因子-IL6可以作为一种广泛的激活标志物，不仅在炎症性应激期间，而且在心理应激期间，可能对治疗方法感兴趣。
Background: The transcription factor nuclear factor interleukin 6 (NF-IL6) is known to be activated by various inflammatory stimuli in the brain. Interestingly, we recently detected NF-IL6-activation within the hypothalamus-pituitary-adrenal (HPA)-axis of rats after systemic lipopolysaccharide (LPS)-injection. Thus, the aim of the present study was to investigate whether NF-IL6 is activated during either, inflammatory, or psychological stress in the rat brain.Methods: Rats were challenged with either the inflammatory stimulus LPS (100 mu g/kg, i.p.) or exposed to a novel environment. Core body temperature (Tb) and motor activity were monitored using telemetry, animals were killed at different time points, brains and blood removed, and primary cell cultures of the anterior pituitary lobe (AL) were investigated. Analyses were performed using immunohistochemistry, RT-PCR, and cytokine-specific bioassays.Results: Stress stimulation by a novel environment increased NF-IL6-immunoreactivity (IR) in the pituitary's perivascular macrophages and hypothalamic paraventricular cells and a rise in Tb lasting approximately 2 h. LPS stimulation lead to NF-IL6-IR in several additional cell types including ACTH-IR-positive corticotrope cells in vivo and in vitro. Two other proinflammatory transcription factors, namely signal transducer and activator of transcription (STAT) 3 and NF kappa B, were significantly activated and partially colocalized with NF-IL6-IR in cells of the AL only after LPS-stimulation, but not following psychological stress. In vitro NF-IL6-activation was associated with induction and secretion of TNF alpha in folliculostellate cells, which could be antagonized by the JAK-STAT-inhibitor AG490.Conclusions: We revealed, for the first time, that NF-IL6 activation occurs not only during inflammatory LPS stimulation, but also during psychological stress, that is, a novel environment. Both stressors were associated with time-dependent activation of NF-IL6 in different cell types of the brain and the pituitary. Moreover, while NF-IL6-IR was partially linked to STAT3 and NF kappa B activation, TNF alpha production, and ACTH-IR after LPS stimulation; this was not the case after exposure to a novel environment, suggesting distinct underlying signaling pathways. Overall, NF-IL6 can be used as a broad activation marker in the brain and might be of interest for therapeutic approaches not only during inflammatory but also psychological stress.