Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1β on long term potentiation in rat dentate gyrus
Activation of p38 plays a pivotal role in the inhibitory effect of lipopolysaccharide and interleukin-1β on long term potentiation in rat dentate gyrus
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DOI：
10.1074/jbc.m301938200
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发表时间：
2003-05-23
影响因子：
4.8
通讯作者：
Lynch, MA
中科院分区：
文献类型：
--
作者：
Kelly, A;Vereker, E;Lynch, MA
脂多糖（LPS），革兰氏阴性菌的细胞壁的一个组成部分，已被证明可以诱导外周和中枢的深刻变化。最近有报道称，腹腔注射LPS可抑制穿通通路-颗粒细胞突触的长时程增强（LTP），这种作用与促炎细胞因子白细胞介素-1 β（IL-1 β）浓度的增加有关。LPS诱导的作用可被caspase-1的抑制所消除，表明IL-1 β可能介导LPS的作用。在此，我们报道了LPS和IL-1 β诱导的LTP抑制与海马和内嗅皮质中应激活化蛋白激酶p38的刺激相结合，并且这种作用被p38抑制剂SB 203580消除，而LPS的作用在C57 BL/6 IL-1 RI（-/-）小鼠中显著减弱。数据还表明，转录因子核因子κ B（NF κ B）的激活可能起作用，因为NF κ B抑制剂SN 50减弱了LPS和IL-1 β对LTP的抑制作用;一致地，LPS和IL-1 β导致内嗅皮层NF κ B的激活。我们认为，这些LPS和IL-1 β诱导的变化的一个后果是在齿状回谷氨酸释放的妥协，这是耦合与LTP的抑制。该证据与LPS诱导的LTP损伤由IL-1 β介导并且是p38激活的结果的观点一致。
Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, has been shown to induce profound changes both peripherally and centrally. It has recently been reported that intraperitoneal injection of LPS inhibited long term potentiation (LTP) in perforant path-granule cell synapses and that this effect was coupled with an increase in the concentration of the proinflammatory cytokine, interleukin-1beta (IL-1beta). The LPS-induced effects were abrogated by inhibition of caspase-1, suggesting that IL-1beta may mediate the effects of LPS. Here we report that the inhibition of LTP induced by LPS and IL-1beta was coupled with stimulation of the stress-activated protein kinase p38 in hippocampus and entorhinal cortex and that this effect was abrogated by the p38 inhibitor SB203580, while the effect of LPS was markedly attenuated in C57BL/6 IL-1RI(-/-) mice. The data also indicate that activation of the transcription factor, nuclear factor kappaB (NFkappaB), may play a role, since the inhibitory effect of LPS and IL-1beta on LTP was attenuated by the NFkappaB inhibitor, SN50; consistently, LPS and IL-1beta led to activation of NFkappaB in entorhinal cortex. We suggest that one consequence of these LPS- and IL-1beta-induced changes is a compromise in glutamate release in dentate gyrus, which was coupled with the inhibition of LTP. The evidence is consistent with the idea that the LPS- induced impairment in LTP is mediated by IL-1beta and is a consequence of activation of p38.