Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist.
Inhibitory effects of endotoxin on LH secretion in the ovariectomized monkey are prevented by naloxone but not by an interleukin-1 receptor antagonist.
复制标题
内毒素对去势猴 LH 分泌的抑制作用可以被纳洛酮阻止，但不能被白细胞介素 1 受体拮抗剂阻止。
DOI：
10.1159/000026415
复制
发表时间：
2000
影响因子：
2.4
通讯作者：
Ferin,M
中科院分区：
文献类型：
--
作者：
Xiao,E;Xia-Zhang,L;Ferin,M
内毒素(脂多糖)是革兰氏阴性菌的致病成分，是细胞因子中枢性释放的重要诱因。本研究的目的是在非人类灵长类动物模型中评价全身应用内毒素对黄体生成素和皮质醇分泌的影响，并探讨这些内分泌作用是否通过使用白介素1受体拮抗剂(IL-1ra)的中枢性释放的白介素1(IL-1)所介导。另一个目的是使用阿片类拮抗剂纳洛酮来研究内源性阿片肽是否介导了内毒素的内分泌效应。这些实验是在长期去卵巢的恒河猴身上进行的。每隔15分钟采集一次用于激素测定的血样，持续8小时，其中包括3小时的基准期。由于IL-1ra在猴子体内的有效中枢剂量尚不清楚，在第一个实验中，我们测试了几种剂量的这种拮抗剂在预防中央注射IL-1α的效果方面的效力，这是一种已知的抑制黄体生成素和刺激皮质醇释放的细胞因子。将IL-1α单独或与不同剂量的IL-1ra(30~180μg/h i.c.v)合用或单独脑室注射IL-1μ(4.2min/30min)30min。IL-1ra在IL-1前1h开始输注，并持续至实验期。如先前报道的那样，IL-1α对黄体生成素有显著的抑制作用，从3小时基线到5小时达到36.5±3.3%(均值±SE)。这种抑制作用可被180µg/h剂量的IL-1ra逆转(5h时为82.5±3.8%；生理盐水与生理盐水相比)，但不能与较低剂量的IL-1ra共同处理。IL-1刺激皮质醇释放达165.9±7.7%，但IL-1ra可阻止皮质醇释放增加(66.6±8.9%；P<；0.05 vs IL-1，NS vs生理盐水)。实验二：静脉注射脂多糖(50μg)、单独注射或联合脑室注射IL-1ra。脂多糖诱导的促黄体生成素分泌显著减少(57.1±5.2%)。侧脑室注射IL-1ra不能逆转上述效应(52.5±9.6%)。这种刺激作用不受IL-1ra的影响(178.3±13.4vs.166.9±5.7%)。IL-1ra单独作用不明显。在实验3中，我们研究了阿片类拮抗剂纳洛酮是否能逆转内毒素的内分泌作用。内毒素(50μg)和纳洛酮(5 mg静注+5 mg/h)均静脉滴注。纳洛酮能有效阻止内毒素对黄体生成素的抑制作用(124.6±22.1%，生理盐水比生理盐水)，但不能阻止皮质醇的增加(166.7±16.7%比生理盐水比内毒素)。纳洛酮单独对黄体生成素或皮质醇的分泌没有显著影响。这些数据表明，在去卵巢的猴子中，全身性炎症/免疫样应激刺激强烈抑制促黄体生成素的分泌，同时刺激皮质醇的释放。虽然已知内毒素会影响中枢细胞因子的释放，但这些内分泌作用并不需要中枢IL-1在灵长类动物中的中介作用。相比之下，内源性阿片途径似乎参与了这一过程。
Endotoxin (lipopolysaccharides, LPS), the pathogenic moiety of gram-negative bacteria, is a well-known trigger for the central release of cytokines. The objective of this study is to evaluate the effects of systemic endotoxin administration on LH and cortisol secretion in a non-human primate model and to investigate whether these endocrine effects are mediated by centrally released interleukin-1 (IL-1) using the receptor antagonist to IL-1 (IL-1ra). An additional objective is to investigate whether endogenous opioid peptides mediate these endocrine effects of LPS, using the opiate antagonist naloxone. The experiments were performed in long-term-ovariectomized rhesus monkeys. Blood samples for hormone determination were obtained at 15-min intervals for a period of 8 h, which included a 3-hour baseline period. Since the effective central dose of IL-1ra in the monkey was unknown, in the first experiment we tested the potency of several doses of this antagonist in preventing the effects of centrally administered IL-1α, a cytokine which is known to inhibit LH and stimulate cortisol release. Rhesus monkeys received a 30-min intracerebroventricular infusion of IL-1α (4.2 μg/30 min) alone or together with various doses of IL-1ra (30–180 μg/h i.c.v.). IL-1ra infusion was initiated 1 h before IL-1 and extended over the experimental period. As previously reported, IL-1α induced a significant inhibition of LH, to 36.5 ± 3.3% (mean ± SE) by 5 h as a percentage from the 3-hour baseline. This inhibitory effect was reversed by cotreatment with the 180 µg/h dose of IL-1ra (to 82.5 ± 3.8% by 5 h; NS vs. saline) but not with the lower doses. IL-1 stimulated cortisol release to 165.9 ± 7.7%, but this increase was prevented by IL-1ra (66.6 ± 8.9%; p < 0.05 vs. IL-1, NS vs. saline). In the second experiment, LPS (50 μg) was administered intravenously, alone or in combination with intracerebroventricular IL-1ra infusion. LPS induced a significant decrease in LH secretion (to 57.1 ± 5.2%). These effects were not reversed by intracerebroventricular administration of IL-1ra (52.5 ± 9.6%). Cortisol secretion increased in response to LPS, but this stimulatory effect was not affected by IL-1ra (178.3 ± 13.4 vs. 166.9 ± 5.7%). There were no effects of IL-1ra alone. In experiment 3, we investigated whether the opiate antagonist naloxone reverses the endocrine effects of endotoxin. Both LPS (50 μg) and naloxone (5-mg bolus + 5 mg/h) were infused intravenously. Naloxone was effective in preventing the inhibitory effect of LPS on LH (to 124.6 ± 22.1%, NS vs. saline) but not the increase in cortisol (to 166.7 ± 16.7%; p < 0.05 vs. saline, NS vs. LPS). Naloxone alone has no significant effect on LH or cortisol secretion. These data demonstrate that, in the ovariectomized monkey, a systemic inflammatory/immune- like stress challenge acutely inhibits tonic LH secretion while concomitantly stimulating cortisol release. Although endotoxin is known to affect central cytokine release, these endocrine effects do not require a mediatory role of central IL-1 in the primate. In contrast, endogenous opioid pathways appear to be involved in this process.