IL-1β stimulates COX-2 dependent PGE₂ synthesis and CGRP release in rat trigeminal ganglia cells.
IL-1β stimulates COX-2 dependent PGE₂ synthesis and CGRP release in rat trigeminal ganglia cells.
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DOI：
10.1371/journal.pone.0017360
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发表时间：
2011-03-04
期刊：
影响因子：
3.7
通讯作者：
Reuter U
中科院分区：
文献类型：
--
作者：
Neeb L;Hellen P;Boehnke C;Hoffmann J;Schuh-Hofer S;Dirnagl U;Reuter U
促炎细胞因子如白细胞介素-1β (IL-1β)与偏头痛和炎症性疼痛的病理生理有关。三叉神经节和降钙素基因相关肽（CGRP）是原发性头痛病理生理的重要组成部分。减少CGRP释放的5-HT1B/D受体激动剂和环氧化酶（COX）抑制剂可以中止三叉介导的疼痛。然而，三叉神经节内COX的细胞来源以及COX与CGRP的相互作用尚不清楚。1. 我们用原代培养的大鼠三叉神经节细胞来评估IL-1β是否能诱导COX-2的表达以及哪些细胞表达COX-2。IL-1β刺激引起COX-2的剂量和时间依赖性诱导，而不是COX-1 mRNA的诱导。免疫组化显示COX-2蛋白在神经元和神经胶质细胞中表达。2. IL-1β刺激后4小时前列腺素E2 （PGE2）释放，可被选择性COX-2（帕瑞昔布）和非选择性COX-2抑制剂（吲哚美辛）终止。3. 在PGE2刺激后1小时和IL-1β刺激后24小时观察到CGRP释放的诱导，表明功能性神经元的激活。免疫组化显示三叉神经细胞为CGRP的来源。IL-1β诱导的CGRP释放被帕瑞昔布和吲哚美辛阻断，而5-HT1B/D受体激动剂舒马匹坦没有作用。我们确定了三叉神经节神经元中细胞因子诱导CGRP释放的COX-2依赖途径，该途径不受5-HT1B/D受体激活的影响。IL-β激活三叉神经节中的神经元和胶质细胞导致这些细胞中COX-2的表达升高。新合成的PGE2（通过COX-2）反过来激活三叉神经释放CGRP。这些发现支持了三叉神经节中胶质-神经元的相互作用，并证明了COX-2和CGRP之间的顺序联系。该结果有助于解释COX-2抑制剂在偏头痛中的作用机制。
Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE2) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE2 and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE2 (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine.
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影响因子：
7.4
作者：
Fanciullacci, Marcello;Alessandri, Massimo;Michelacci, Sergio
通讯作者：
Michelacci, Sergio
DOI：
10.1523/jneurosci.3795-08.2008
发表时间：
2008-12-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Binshtok AM;Wang H;Zimmermann K;Amaya F;Vardeh D;Shi L;Brenner GJ;Ji RR;Bean BP;Woolf CJ;Samad TA
通讯作者：
Samad TA
DOI：
10.1152/ajpregu.00347.2002
发表时间：
2002-11-01
影响因子：
2.8
作者：
Ivanov, AI;Pero, RS;Romanovsky, AA
通讯作者：
Romanovsky, AA
影响因子：
7.3
作者：
CUNHA, FQ;POOLE, S;FERREIRA, SH
通讯作者：
FERREIRA, SH
影响因子：
7.3
作者：
Cunha, JM;Cunha, FQ;Ferreira, SH
通讯作者：
Ferreira, SH