Prostaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence.
Prostaglandins mediate the ACTH response to interleukin-1-beta instilled into the hypothalamic median eminence.
复制标题
前列腺素介导 ACTH 对注入下丘脑正中隆起的白细胞介素 1-β 的反应。
DOI：
10.1159/000126777
复制
发表时间：
1994
影响因子：
4.1
通讯作者：
Sharp,BM
中科院分区：
文献类型：
--
作者：
McCoy,JG;Matta,SG;Sharp,BM
白细胞介素-1 β（IL-1β）是一种强有力的促ACTH分泌素，能激活下丘脑CRH的释放。将IL-1β直接注射到缺乏血脑屏障的下丘脑正中隆起（ME）中，已显示可快速诱导ACTH分泌。因此，ME可能是循环IL-1β进入大脑以刺激CRH并因此刺激ACTH分泌的部位。为了进一步评估这一假设，开发了一种角度立体定位方法来定位IL-1β向ME的扩散，并将注射物与下丘脑室旁核（PVN）（另一个建议的IL-1作用部位）最佳分离。[125 I]-IL-1β扩散研究（100 nl递送60 s）显示，97%保留在下丘脑腹面200 µm内，87%包含在矢状面注射部位550 µm半径内。其他大鼠接受重组人IL-1β（0.2-25.0 ng/100 nl）注入ME（ME内）。与之前报道的剂量相比，低得多的IL-1β剂量（0.5 ng，p < 0.001）可显着升高血浆ACTH水平。反应似乎是剂量依赖性的，2.0 ng IL-1β最大刺激ACTH。此外，ME中免疫细胞化学标记的CRH在ME内IL-1β后显著减少。吲哚美辛是一种前列腺素（PG）合成的抑制剂，已显示可阻断来自下丘脑外植体的IL-1 β对CRH分泌的诱导以及对静脉内IL-1β的ACTH应答。因此，使用吲哚美辛来确定PG是否是递送到ME中的IL-1β的ACTH应答的介质。当低剂量的吲哚美辛（lmg/kg i. v.）在ME内IL-1β（25 ng）前20分钟给予。最后，血浆促肾上腺皮质激素升高，在剂量依赖性的方式由内ME管理的PG。促肾上腺皮质激素对前列腺素E2的反应等级为：CSF < 0.5 μg（p < 0.001）= 2.0 μg < 4.0 μg（p < 0.05）。对PGF 2 α的反应为：CSF < 0.5 µg（p < 0.001）< 2.0 µg（p < 0.05）= 4.0 µg。由于这些PG似乎激活不同的第二信使系统，因此单独或联合给予每种PG的次最大剂量。由于PGE 2和PGF 2 α（各0.5 µg）联合给药后的总体ACTH水平不高于两种单独给药的总和，因此，反应的加和性而非协同作用是明显的。总之，ACTH对IL-1β进入ME的反应似乎是由局部肾上腺素介导的。
Interleukin-1β (IL-1β) is a potent ACTH secretagogue which activates the release of hypothalamic CRH. Direct injections of IL-1β into the hypothalamic median eminence (ME), a site which lacks a blood-brain barrier, has been shown to rapidly induce ACTH secretion. Therefore, the ME is a likely site whereby circulating IL-1β can access the brain to stimulate CRH and, consequently, ACTH secretion. To further evaluate this hypothesis, an angular stereotaxic approach was developed to localize the spread of IL-1β to the ME and to optimally separate the injectate from the hypothalamic paraventricular nucleus (PVN), another proposed site of IL-1 action. Studies of the diffusion of [125I]-IL-1β (100 nl delivered over 60 s) showed that 97% remained within 200 µm of the ventral surface of the hypothalamus and 87% was contained within a radius of 550 µm of the injection site in the sagittal plane. Additional rats received recombinant human IL-1β (0.2-25.0 ng in 100 nl) into the ME (intra-ME). Plasma ACTH levels were significantly elevated by a much lower dose (0.5 ng, p < 0.001) of IL-1β than that previously reported. Responses appeared to be dose-dependent and ACTH was maximally stimulated by 2.0 ng IL-1β. Also, immunocytochemically labelled CRH in the ME was markedly depleted after intra-ME IL-1β. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, has been shown to block both the induction of CRH secretion by IL-lβ from hypothalamic explants, as well as the ACTH response to intravenous IL-1β. Thus, indomethacin was used to determine whether PGs are mediators of the ACTH response to IL-1β delivered into the ME. The ACTH response was abolished (p < 0.005) when a low dose of indomethacin (1 mg/kg i.v.) was administered 20 min before intra-ME IL-1β (25 ng). Finally, plasma ACTH was elevated in a dose-dependent manner by the intra-ME administration of PGs. The hierarchy of ACTH responses to PGE2were: CSF < 0.5 µg (p < 0.001) = 2.0 µg < 4.0 µg(p < 0.05). Responses to PGF2αwere: CSF < 0.5 µg (p < 0.001) < 2.0 µg (p < 0.05) = 4.0 µg. Since these PGs appear to activate different second-messenger systems, a submaximal dose of each was administered alone or in combination. Additivity of the response, rather than synergy, was evident, since the overall ACTH level in response to the combination of PGE2and PGF2α(0.5 µg each) was no greater than the sum of the two separate treatments. In summary, the ACTH response to IL-1β delivered into the ME appears to be mediated by local prostaglandins.