Takao T, Hashimoto K, De Souza E B
Second Department of Internal Medicine, Kochi Medical School, Nankoku, Japan.
Brain Behav Immun. 1995 Dec;9(4):276-91. doi: 10.1006/brbi.1995.1027.
We summarize data from some of our recent studies on in vitro and in vivo modulation of interleukin-1 (IL-1) receptors in the mouse brain-endocrine-immune axis by stress and infection. Ether-laparotomy stress in mice resulted in a selective increase in pituitary IL-1 receptors and a significant decrease in pituitary receptors for corticotropin-releasing factor (CRF), a major regulator of the endocrine response to stress. Intraperitoneal injection of rat/human CRF mimicked the effects of stress and resulted in a dramatic increase in [125I]IL-1alpha binding in the pituitary; [125I]IL-1alpha binding in the hippocampus, spleen, and testis was unaffected by stress or CRF treatment. Glucocorticoid treatment with dexamethasone alone did not alter [125I]IL-1alpha binding but significantly inhibited CRF-induced upregulation of IL-1 receptors in the pituitary. The intracellular mechanism(s) involved in stress and CRF-induced upregulation of IL-1 receptors in the pituitary gland were examined by evaluating the effects of treatment of AtT-20 mouse pituitary corticotroph cells with a variety of neuroendocrine mediators of stress. CRF, forskolin, and isoproterenol (beta2 adrenergic receptor agonist) produced dose-dependent increases in cAMP production and [125I]IL-1alpha binding. In contrast, somatostatin and dexamethasone significantly inhibited CRF-stimulated increase of cAMP production and [125I]IL-1alpha binding, suggesting a primary role for cAMP in the regulation of pituitary IL-1 receptors. Next, we investigated the modulation of IL-1beta levels and IL-1 receptors following infection of mice with the endotoxin, lipopolysaccharide (LPS). Acute administration of low doses of endotoxin (30 mu g LPS/mouse) dramatically increased IL-1beta levels and reciprocally decreased [125I]IL-1alpha binding in peripheral tissues (pituitary, testis, liver, and spleen) but not in brain (hippocampus). This effect appeared to be dose related since higher doses of endotoxin (300 mu g LPS/mouse) significantly decreased [125I]IL-1alpha binding in both peripheral tissues and brain. Endotoxin induced modulation of the IL-1 system was also dependent on the treatment regimen since two low-dose LPS injections (at 0 and 12 h) increased IL-1beta concentrations and decreased [125I]IL-1alpha binding in both central and peripheral tissues. These data provide further support for a role for IL-1 in coordinating brain-endocrine-immune responses to stress and infection.
我们总结了近期一些关于应激和感染对小鼠脑-内分泌-免疫轴中白细胞介素-1（IL-1）受体进行体外和体内调节的研究数据。小鼠的乙醚剖腹手术应激导致垂体IL-1受体选择性增加，而垂体中促肾上腺皮质激素释放因子（CRF）的受体显著减少，CRF是应激时内分泌反应的主要调节因子。腹腔注射大鼠/人CRF模拟了应激的作用，导致垂体中[125I]IL-1α结合显著增加；海马、脾脏和睾丸中的[125I]IL-1α结合不受应激或CRF处理的影响。单独用地塞米松进行糖皮质激素处理并未改变[125I]IL-1α结合，但显著抑制了CRF诱导的垂体中IL-1受体上调。通过评估用多种应激神经内分泌介质处理AtT-20小鼠垂体促肾上腺皮质激素细胞的效果，研究了应激和CRF诱导垂体中IL-1受体上调所涉及的细胞内机制。CRF、福斯可林和异丙肾上腺素（β2肾上腺素能受体激动剂）使cAMP生成和[125I]IL-1α结合呈剂量依赖性增加。相反，生长抑素和地塞米松显著抑制CRF刺激的cAMP生成增加和[125I]IL-1α结合，表明cAMP在垂体IL-1受体调节中起主要作用。接下来，我们研究了用内毒素脂多糖（LPS）感染小鼠后IL-1β水平和IL-1受体的调节情况。急性给予低剂量内毒素（30μg LPS/小鼠）显著增加IL-1β水平，并相应降低外周组织（垂体、睾丸、肝脏和脾脏）而非脑（海马）中的[125I]IL-1α结合。这种效应似乎与剂量有关，因为更高剂量的内毒素（300μg LPS/小鼠）显著降低了外周组织和脑中的[125I]IL-1α结合。内毒素诱导的IL-1系统调节也取决于处理方案，因为两次低剂量LPS注射（在0和12小时）增加了中枢和外周组织中的IL-1β浓度并降低了[125I]IL-1α结合。这些数据为IL-1在协调脑-内分泌-免疫对应激和感染的反应中的作用提供了进一步支持。
