Rivier C, Vale W
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California 92037.
Endocrinology. 1991 Jul;129(1):384-8. doi: 10.1210/endo-129-1-384.
The in vivo release of ACTH by interleukin-1 alpha (II-1 alpha) is reportedly blocked by acute treatment with indomethacin (indo), suggesting an involvement of endogenous prostaglandins in the effect of cytokines on the hypothalamic-pituitary-adrenal axis. However, indo also increases plasma corticosterone levels, raising the possibility that inhibition of ACTH release is due to suppressive effects of hypercorticolemia rather than to blockade of the stimulatory effects of II-1 alpha. We observed that the iv administration of indo (10 mg/kg) 15 min before II-1 alpha completely abolished the rise in plasma ACTH levels caused by the peripheral injection of this lymphokine to intact rats. At the time of II-1 alpha injection, plasma corticosterone levels were 39 +/- 12 ng/ml in controls and 121 +/- 22 ng/ml in indo-treated animals (P less than or equal to 0.01). In contrast, implantation of intact rats with indo pellets (which delivered 30 micrograms drug/h) 28 h before II-1 only partially interfered with II-1-induced ACTH secretion. In these rats plasma corticosterone levels before II-1 alpha injection were 29 +/- 14 ng/ml in controls and 66 +/- 18 ng/ml in rats implanted with indo pellets (P less than or equal to 0.05). To determine whether the effect of indo was due to corticosteroid feedback or represented a modulating action of prostaglandins themselves, a similar series of experiments was carried out in adrenalectomized rats. In the absence of corticoid replacement therapy, acute treatment with indo did not measurably interfere with the stimulatory effect of II-1 alpha. In contrast, indo blunted, but did not abolish, the effect of II-1a in ADX rats pretreated with corticosterone or dexamethasone to normalize basal ACTH levels. We conclude that the acute ability of indomethacin to totally block II-1-induced ACTH secretion by intact rats appears to be primarily mediated through corticosteroid feedback. However, results obtained when a similar experiment was carried out in adrenalectomized/corticosteroid-treated rats suggest, although they do not prove, that the ability of II-1 alpha to activate the hypothalamic-pituitary-adrenal axis may be partially dependent on the release of prostaglandins.
据报道，白细胞介素-1α（IL-1α）在体内促肾上腺皮质激素（ACTH）的释放可被吲哚美辛（消炎痛，indo）的急性处理所阻断，这表明内源性前列腺素参与了细胞因子对下丘脑-垂体-肾上腺轴的作用。然而，消炎痛也会使血浆皮质酮水平升高，这增加了ACTH释放受抑制是由于高皮质醇血症的抑制作用而非对IL-1α刺激作用的阻断的可能性。我们观察到，在给完整大鼠外周注射这种淋巴因子前15分钟静脉注射消炎痛（10毫克/千克），可完全消除血浆ACTH水平的升高。在注射IL-1α时，对照组血浆皮质酮水平为39±12纳克/毫升，消炎痛处理组动物为121±22纳克/毫升（P≤0.01）。相比之下，在给完整大鼠植入消炎痛微丸（每小时释放30微克药物）28小时后注射IL-1α，仅部分干扰了IL-1诱导的ACTH分泌。在这些大鼠中，注射IL-1α前，对照组血浆皮质酮水平为29±14纳克/毫升，植入消炎痛微丸的大鼠为66±18纳克/毫升（P≤0.05）。为了确定消炎痛的作用是由于皮质类固醇反馈还是代表前列腺素本身的调节作用，在肾上腺切除的大鼠中进行了一系列类似实验。在没有皮质激素替代治疗的情况下，消炎痛的急性处理并未明显干扰IL-1α的刺激作用。相反，在肾上腺切除的大鼠中，预先用皮质酮或地塞米松处理以使基础ACTH水平正常化后，消炎痛减弱但并未消除IL-1α的作用。我们得出结论，消炎痛对完整大鼠完全阻断IL-1诱导的ACTH分泌的急性作用似乎主要是通过皮质类固醇反馈介导的。然而，在肾上腺切除/皮质类固醇处理的大鼠中进行类似实验所获得的结果表明，尽管没有证明，但IL-1α激活下丘脑-垂体-肾上腺轴的能力可能部分依赖于前列腺素的释放。
