Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning.
Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning.
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DOI：
10.1016/j.bbi.2011.10.008
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发表时间：
2012-07
影响因子：
15.1
通讯作者：
Johnson, Rodney W.
中科院分区：
文献类型：
--
作者：
Burton, Michael D.;Johnson, Rodney W.
关键词：
在衰老的大脑中，外周免疫刺激引起的促炎细胞因子的过度产生被认为是导致行为病理的原因，然而，很少有研究检验促炎细胞因子的增加是否伴随着细胞因子信号的增加。在这里，我们专注于IL-6作为典型的促炎细胞因子，并使用磷酸化的STAT3作为IL-6信号转导的标志。在最初的研究中，与成人相比，腹腔注射后，衰老小鼠海马区IL-6mRNA以及STAT3激活的幅度和持续时间都增加了。注射内毒素。在老年IL-6−/−小鼠中，脂多糖诱导的STAT3活性的增加被消融，这表明IL-6是老年脑中STAT3活性的关键驱动因素。为了确定IL-6是否激活了经典或反式信号通路，在接受内毒素注射之前，老年小鼠脑室注射了反式信号通路的拮抗剂sgp130。重要的是，sgp130抑制了内毒素诱导的海马区IL-6和STAT3活性的增加。为评价老龄小鼠的海马区功能，脑室注射sgp130和ip。在情景恐惧条件反射的习得阶段后立即进行内毒素刺激，48h后在保留阶段评估不动状态。脂多糖减少了老年小鼠的不动，表明免疫激活干扰了记忆巩固。然而，sgp130阻断了内毒素引起的背景恐惧条件反射的缺陷。综上所述，这些结果表明，外周内毒素攻击后，衰老脑中IL-6反式信号转导增加，sgp130可能对老年人感染相关的神经炎症和认知功能障碍具有保护作用。
Excessive production of pro-inflammatory cytokines in the senescent brain in response to peripheral immune stimulation is thought to induce behavioral pathology, however, few studies have examined if the increase in pro-inflammatory cytokines is accompanied by an increase in cytokine signaling. Here, we focused on IL-6 as a prototypic pro-inflammatory cytokine and used phosphorylated STAT3 as a marker of IL-6 signaling. In an initial study, IL-6 mRNA and the magnitude and duration of STAT3 activation were increased in the hippocampus of senescent mice compared to adults after i.p. injection of LPS. The LPS-induced increase in STAT3 activity was ablated in aged IL-6−/− mice, suggesting IL-6 is a key driver of STAT3 activity in the aged brain. To determine if IL-6 activated the classical or trans-signaling pathway, before receiving LPS i.p., aged mice were injected ICV with sgp130, an antagonist of the trans-signaling pathway. Importantly, the LPS-induced increases in both IL-6 and STAT3 activity in the hippocampus were inhibited by sgp130. To assess hippocampal function, aged mice were injected ICV with sgp130 and i.p. with LPS immediately after the acquisition phase of contextual fear conditioning, and immobility was assessed in the retention phase 48 h later. LPS reduced immobility in aged mice, indicating immune activation interfered with memory consolidation. However, sgp130 blocked the deficits in contextual fear conditioning caused by LPS. Taken together, the results suggest IL-6 trans-signaling is increased in the senescent brain following peripheral LPS challenge and that sgp130 may protect against infection-related neuroinflammation and cognitive dysfunction in the aged.
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DOI：
10.1523/jneurosci.5818-10.2011
发表时间：
2011-03-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Cortese GP;Barrientos RM;Maier SF;Patterson SL
通讯作者：
Patterson SL
影响因子：
15.1
作者：
Chen, Jing;Buchanan, Jessica B.;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.
影响因子：
2.5
作者：
BELLINGER, FP;MADAMBA, SG;SIGGINS, GR
通讯作者：
SIGGINS, GR
DOI：
10.1073/pnas.1531903100
发表时间：
2003-07-22
影响因子：
11.1
作者：
Kiecolt-Glaser, JK;Preacher, KJ;Glaser, R
通讯作者：
Glaser, R
DOI：
10.1046/j.1432-1327.2001.01867.x
发表时间：
2001-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Jostock, T;Müllberg, J;Rose-John, S
通讯作者：
Rose-John, S