Papadopoulos A D, Wardlaw S L
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
J Neuroendocrinol. 1999 Apr;11(4):315-9. doi: 10.1046/j.1365-2826.1999.00327.x.
We and others have previously shown that exogenous alpha-MSH antagonizes the stimulatory effects of the cytokine interleukin (IL)-1 on the hypothalamic-pituitary-adrenal (HPA) axis. It is currently unknown, however, if endogenous alpha-MSH plays a physiological role in regulating the HPA response to IL-1. We have therefore examined the HPA response to IL-1beta in rats pretreated with an affinity purified alpha-MSH antiserum (AS) infused intracerebroventricularly to neutralize endogenous alpha-MSH within the brain. alpha-MSH AS or a similarly purified fraction of normal rabbit serum (NRS) was injected intracerebroventricularly at 16 h and at 1 h prior to the i.c.v. injection of IL-1beta (2 ng or 20 ng) and blood samples were collected through an indwelling atrial catheter. After 2 ng IL-1beta, the adrenocorticotropic hormone (ACTH) response was significantly greater in the alpha-MSH AS treated rats (n = 7) compared to the NRS treated rats (n = 7) (P <0.01); the mean ACTH level rose to a peak of 594+208 pg/ml in the alpha-MSH AS treated rats vs 274+/-122 pg/ml in the NRS treated rats. The area under the ACTH response curve in the alpha-MSH AS treated animals was 181% of that in the NRS treated animals (P<0.05). A significant effect of alpha-MSH AS on the corticosterone response to i.c.v. IL-1beta was also noted during the first 3 h of the study (P<0.05). The mean area under the corticosterone response curve for the first 3 h in the alpha-MSH AS treated animals was 144% of that in the NRS treated animals (P <0.05). After 20 ng IL-1beta, the ACTH response over time was again significantly greater in the alpha-MSH AS treated rats (n=8) compared to the NRS treated rats (n=9) (P<0.02); the mean ACTH level rose to a peak of 673+/-190 pg/ml after alpha-MSH AS vs 490+/-115 pg/ml after NRS. Corticosterone levels rose to a peak of 42+/-3.9 microg/dl in the alpha-MSH AS treated rats vs 37+/-4.6 microg/dl in the NRS treated rats; this difference was not significant. We conclude that the IL-1beta induced stimulation of ACTH is significantly enhanced by antagonizing the activity of alpha-MSH. These results support a physiological role for endogenous alpha-MSH in limiting the HPA response to this inflammatory cytokine.
我们和其他研究人员之前已经表明，外源性α-促黑素（α-MSH）可拮抗细胞因子白细胞介素（IL）-1对下丘脑-垂体-肾上腺（HPA）轴的刺激作用。然而，目前尚不清楚内源性α-MSH在调节HPA对IL-1的反应中是否发挥生理作用。因此，我们研究了在经脑室内注入亲和纯化的α-MSH抗血清（AS）预处理以中和脑内源性α-MSH的大鼠中，HPA对IL-1β的反应。在脑室内注射IL-1β（2 ng或20 ng）前16小时和1小时，经脑室内注射α-MSH AS或同样纯化的正常兔血清（NRS）组分，并通过留置心房导管采集血样。给予2 ng IL-1β后，与NRS处理的大鼠（n = 7）相比，α-MSH AS处理的大鼠（n = 7）促肾上腺皮质激素（ACTH）反应显著增强（P <0.01）；α-MSH AS处理的大鼠中ACTH平均水平升至峰值594+208 pg/ml，而NRS处理的大鼠中为274+/-122 pg/ml。α-MSH AS处理动物的ACTH反应曲线下面积是NRS处理动物的181%（P<0.05）。在研究的前3小时内，还观察到α-MSH AS对脑室内注射IL-1β引起的皮质酮反应有显著影响（P<0.05）。α-MSH AS处理动物前3小时皮质酮反应曲线下的平均面积是NRS处理动物的144%（P <0.05）。给予20 ng IL-1β后，与NRS处理的大鼠（n = 9）相比，α-MSH AS处理的大鼠（n = 8）随时间的ACTH反应再次显著增强（P<0.02）；α-MSH AS处理后ACTH平均水平升至峰值673+/-190 pg/ml，而NRS处理后为490+/-115 pg/ml。α-MSH AS处理的大鼠中皮质酮水平升至峰值42+/-3.9 μg/dl，而NRS处理的大鼠中为37+/-4.6 μg/dl；这种差异不显著。我们得出结论，通过拮抗α-MSH的活性，IL-1β诱导的ACTH刺激显著增强。这些结果支持内源性α-MSH在限制HPA对这种炎性细胞因子反应中发挥生理作用。
