Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus
Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus
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DOI：
10.1074/jbc.m412170200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Lynch, MA
中科院分区：
文献类型：
--
作者：
Nolan, Y;Maher, FO;Lynch, MA
有充分证据表明，老年动物海马体的长时程增强 (LTP) 受损。导致这种损伤的变化包括海马促炎细胞因子白细胞介素-1β (IL-1β) 浓度的增加以及 IL-1β 诱导的信号传导的增加。在这项研究中，我们调查了这些变化是否是抗炎细胞因子 IL-4 浓度降低和 IL-4 刺激信号传导减少的结果。我们报道功能性 IL-4 受体在齿状回的颗粒细胞上表达，并且受体激活导致 JAK1 和 STAT6 磷酸化。海马 IL-4 浓度随着年龄的增长而降低，并且伴随着 JAK1 和 STAT6 磷酸化的降低。证据表明，IL-4 调节 IL-1β mRNA 和蛋白质的表达，并减轻 IL-1β 诱导的 LTP 损伤以及 JNK 和 c-Jun 磷酸化。我们认为，如果海马 IL-4 浓度的降低显着导致与年龄相关的 LTP 损伤，那么 IL-4 的恢复应该可以恢复 LTP。为了测试这一点，我们用 VP015（掺有磷脂酰丝氨酸的磷脂微粒）治疗大鼠，这会增加海马中 IL-4 的浓度。数据表明，VP015诱导的老年大鼠和脂多糖（LPS）治疗大鼠海马中IL-4浓度的增加伴随着与年龄相关的和LPS诱导的穿通路径颗粒细胞突触中LTP损伤的逆转。我们认为促炎和抗炎反应之间的相互作用对老年大鼠海马的突触功能有显着影响。
It is well documented that long term potentiation (LTP) is impaired in the hippocampus of the aged animal. Among the changes that contribute to this impairment is an increase in hippocampal concentration of the pro-inflammatory cytokine interleukin-1beta (IL-1beta), and increased IL-1beta-induced signaling. In this study we investigated the possibility that these changes were a consequence of decreased concentration of the anti-inflammatory cytokine, IL-4, and decreased IL-4-stimulated signaling. We report that functional IL-4 receptors are expressed on granule cells of the dentate gyrus and that receptor activation results in phosphorylation of JAK1 and STAT6. Hippocampal IL-4 concentration was decreased with age, and this was accompanied by a decrease in phosphorylation of JAK1 and STAT6. The evidence indicates that IL-4 modulates expression of IL-1beta mRNA and protein and that it attenuates IL-1beta-induced impairment of LTP and phosphorylation of JNK and c-Jun. We argued that, if a decrease in hippocampal IL-4 concentration significantly contributed to the age-related impairment in LTP, then restoration of IL-4 should restore LTP. To test this, we treated rats with VP015(phospholipid microparticles-incorporating phosphatidylserine), which increases IL-4 concentration in hippocampus. The data indicate that the VP015-induced increase in IL-4 concentration in hippocampus of aged rats and lipopolysaccharide (LPS)-treated rats was accompanied by a reversal of the age-related and LPS-induced impairment in LTP in perforant path granule cell synapses. We propose that interplay between pro-inflammatory and anti-inflammatory responses impact significantly on synaptic function in the hippocampus of the aged rat.