Papadopoulos A D, Wardlaw S L
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Neuroimmunomodulation. 2000;8(1):39-44. doi: 10.1159/000026451.
Endotoxin and the inflammatory cytokines interleukin (IL)-1 and IL-6 are potent activators of the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies in the rodent and in the primate have shown that the responses of the HPA axis to endotoxin and to IL-1 were enhanced by gonadectomy and attenuated by testosterone or estradiol replacement. The mechanisms underlying these observations are unclear, but there is evidence that gonadal steroids have direct inhibitory effects on IL-6 synthesis and release. Since endotoxin and IL-1 both stimulate IL-6, the question arises as to whether the sex-steroid-induced suppression of the HPA response to endotoxin and IL-1 results solely from decreased IL-6 release, or whether other mediators are involved.
We have therefore examined the ACTH and corticosterone responses to IL-6 in intact and castrated male rats with and without testosterone replacement. Animals were castrated 2 weeks prior to study; testosterone was replaced by subcutaneous Silastic capsules. Four days prior to study, an indwelling right atrial catheter was implanted. Blood samples for ACTH and corticosterone radioimmunoassays were collected through the catheter 0, 20, 40, 60, 120 and 180 min after intravenous injection of recombinant human IL-6 (500 ng).
IL-6 stimulated ACTH and corticosterone release in all groups, with peak stimulation occurring within the first hour. The release of both ACTH and corticosterone was significantly attenuated in the intact (n = 9) and testosterone-replaced (n = 5) animals compared to the castrated animals without replacement (n = 7). Peak ACTH levels were 340 +/- 58 and 133 +/- 41 pg/ml in the intact and testosterone-replaced animals versus 678 +/- 170 pg/ml in the castrated animals (p < 0.02). Peak corticosterone levels were 29 +/- 4.7 and 30 +/- 4.2 microg/dl in the intact and testosterone-replaced animals versus 47 +/- 5.8 microg/dl in the castrated animals (p < 0.05).
We conclude that testosterone attenuates the response of the HPA axis to IL-6 in the rat. This would indicate that other mechanisms, in addition to the inhibition of IL-6 release, are responsible for restraining the HPA response to inflammatory stimuli in the presence of gonadal steroids.
内毒素以及炎性细胞因子白细胞介素（IL）-1和IL-6是下丘脑-垂体-肾上腺（HPA）轴的强效激活剂。先前对啮齿动物和灵长类动物的研究表明，性腺切除术可增强HPA轴对内毒素和IL-1的反应，而睾酮或雌二醇替代则可减弱这种反应。这些观察结果背后的机制尚不清楚，但有证据表明性腺类固醇对IL-6的合成和释放具有直接抑制作用。由于内毒素和IL-1均刺激IL-6，因此问题在于性腺类固醇诱导的HPA轴对内毒素和IL-1反应的抑制是否仅源于IL-6释放的减少，或者是否涉及其他介质。
因此，我们研究了完整和去势雄性大鼠在有或没有睾酮替代的情况下，对IL-6的促肾上腺皮质激素（ACTH）和皮质酮反应。在研究前2周对动物进行去势；通过皮下植入硅橡胶胶囊来替代睾酮。在研究前4天，植入一根留置的右心房导管。在静脉注射重组人IL-6（500 ng）后的0、20、40、60、120和180分钟，通过导管采集用于ACTH和皮质酮放射免疫分析的血样。
IL-6刺激了所有组中ACTH和皮质酮的释放，在第一小时内达到刺激峰值。与未进行替代的去势动物（n = 7）相比，完整动物（n = 9）和接受睾酮替代的动物（n = 5）中ACTH和皮质酮的释放均显著减弱。完整动物和接受睾酮替代的动物中ACTH的峰值水平分别为340±58和133±41 pg/ml，而去势动物中的峰值水平为678±170 pg/ml（p < 0.02）。完整动物和接受睾酮替代的动物中皮质酮的峰值水平分别为29±4.7和30±4.2 μg/dl，而去势动物中的峰值水平为47±5.8 μg/dl（p < 0.05）。
我们得出结论，睾酮可减弱大鼠HPA轴对IL-6的反应。这表明，除了抑制IL-6释放外，还有其他机制负责在存在性腺类固醇的情况下抑制HPA轴对炎症刺激的反应。
