A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain
A pivotal role for interleukin-4 in atorvastatin-associated neuroprotection in rat brain
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DOI：
10.1074/jbc.m707442200
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发表时间：
2008-01-25
影响因子：
4.8
通讯作者：
Lynch, Marina A.
中科院分区：
文献类型：
--
作者：
Clarke, Rachael M.;Lyons, Anthony;Lynch, Marina A.
炎症变化，其特征在于增加促炎细胞因子的产生和上调相应的信号传导途径，已被描述在老年大鼠和大鼠的大脑中与有效的免疫调节分子脂多糖（LPS）。这些变化与海马长时程增强（LTP）的缺陷相结合。证据表明，抗炎药可以减弱脂多糖诱导的和年龄相关的海马白细胞介素-1 β（IL-1 β）浓度增加，从而导致LTP的恢复。在这里，我们报告说，阿托伐他汀，作为3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂家族的成员，发挥强大的抗炎作用，在大脑中，这些作用是由IL-4介导的，独立于其降胆固醇的行动。用阿托伐他汀治疗大鼠增加了从LPS治疗和老年大鼠制备的海马组织中的IL-4浓度，并消除了促炎细胞因子、干扰素-γ（IFN-γ）和IL-1 β的年龄相关性和LPS诱导的增加，以及伴随的LTP缺陷。在IL-4（-/-）小鼠制备的组织中，阿托伐他汀对LPS诱导的IFN γ和IL-1 β升高无影响。通过分析主要组织相容性复合体II的表达来评估，在LPS处理的老年大鼠中IL-1 β的增加与小胶质细胞活化的增加相关，并且证据表明IFN γ可能触发这种活化。我们认为阿托伐他汀的主要作用是增加IL-4，而IL-4拮抗IFN γ的作用、小胶质细胞活化的相关增加以及随后的级联反应。
Inflammatory changes, characterized by an increase in proinflammatory cytokine production and up-regulation of the corresponding signaling pathways, have been described in the brains of aged rats and rats treated with the potent immune modulatory molecule lipopolysaccharide ( LPS). These changes have been coupled with a deficit in long-term potentiation ( LTP) in hippocampus. The evidence suggests that anti-inflammatory agents, which attenuate the LPS-induced and age-associated increase in hippocampal interleukin-1 beta (IL-1 beta) concentration, lead to restoration of LTP. Here we report that atorvastatin, a member of the family of agents that act as inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, exerts powerful anti-inflammatory effects in brain and that these effects are mediated by IL-4 and independent of its cholesterol-lowering actions. Treatment of rats with atorvastatin increased IL-4 concentration in hippocampal tissue prepared from LPS-treated and aged rats and abrogated the age-related and LPS-induced increases in pro-inflammatory cytokines, interferon-gamma ( IFN gamma) and IL-1 beta, and the accompanying deficit in LTP. The effect of atorvastatin on the LPS-induced increases in IFN gamma and IL-1 beta was absent in tissue prepared from IL-4(-/-) mice. The increase in IL-1 beta in LPS-treated and aged rats is associated with increased microglial activation, assessed by analysis of major histocompatibility complex II expression, and the evidence suggests that IFN gamma may trigger this activation. We propose that the primary effect of atorvastatin is to increase IL-4, which antagonizes the effects of IFN gamma, the associated increase in microglial activation, and the subsequent cascade of events.