Schöbitz B, Sutanto W, Carey M P, Holsboer F, de Kloet E R
Leiden-Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Neuroendocrinology. 1994 Aug;60(2):124-33. doi: 10.1159/000126742.
Lipopolysaccharides (LPS) activate both the immune and the stress response system. The effects of these bacterial endotoxins involve the release of interleukin 1 (IL1) and other cytokines, which in turn stimulate the hypothalamic-pituitary-adrenal (HPA) axis. We studied the binding properties of the corticosteroid receptor system, which mediates feedback inhibition of the HPA axis, in two brain areas and in the pituitary gland in rats treated with LPS and recombinant murine IL1 beta. The binding properties of the corticosteroid receptors were determined by Scatchard plot analyses of in vitro cytosolic binding of the tritiated mineralocorticoid receptor (MR) radioligand aldosterone and the tritiated glucocorticoid receptor (GR) ligand RU28362. Tissues were collected 48 h after administration of LPS, including a 24-hour period for depletion of endogenous corticosterone. LPS treatment increased the Kd of [3H]aldosterone of the hippocampal MR 4.3-fold and the apparent maximum binding capacity (Bmax) of [3H]aldosterone by 65% during a time interval when the concentration of corticosterone, the endogenous ligand of both hippocampal MR and GR, was elevated in the intact rat. Thereafter, MR binding properties were not different from vehicle-injected controls, at 96 h, when in intact animals the enhanced HPA activity subsided. GRs, determined by binding of [3H]RU28362, were not affected by LPS. IL1 evoked a 2.7-fold increase in the Kd of the hippocampal MR and a 57% increase in Bmax 3 h after injection into the lateral cerebral ventricle. An autoradiographic procedure revealed that the same treatment with IL1 reduced the retention of the tritiated endogenous MR ligand corticosterone by 40-60% in all pyramidal cell layers and in the dentate gyrus of the hippocampus, when a tracer dose of the steroid was administered that gives rise to a concentration around the Kd of the MR. This reduced in vivo retention of corticosterone is predicted in view of the reduced affinity of hippocampal MRs. The data are consistent with the hypothesis that an impaired feedback of the HPA axis via deficient hippocampal MRs contributes to stimulate corticosterone secretion from the adrenals during infection.
脂多糖（LPS）可激活免疫和应激反应系统。这些细菌内毒素的作用包括白细胞介素1（IL1）和其他细胞因子的释放，进而刺激下丘脑 - 垂体 - 肾上腺（HPA）轴。我们研究了皮质类固醇受体系统的结合特性，该系统介导HPA轴的反馈抑制，研究对象为用LPS和重组鼠IL1β处理的大鼠的两个脑区和垂体。通过对氚标记的盐皮质激素受体（MR）放射性配体醛固酮和氚标记的糖皮质激素受体（GR）配体RU28362的体外胞质结合进行Scatchard图分析，来确定皮质类固醇受体的结合特性。在给予LPS 48小时后收集组织，其中包括24小时耗尽内源性皮质酮的时间段。在完整大鼠中，当海马MR和GR的内源性配体皮质酮浓度升高的时间段内，LPS处理使海马MR的[3H]醛固酮的解离常数（Kd）增加了4.3倍，[3H]醛固酮的表观最大结合容量（Bmax）增加了65％。此后，在96小时时，MR结合特性与注射赋形剂的对照组没有差异，此时在完整动物中增强的HPA活性消退。通过[3H]RU28362的结合来测定的GR不受LPS影响。向侧脑室注射IL1 3小时后，海马MR的Kd增加了2.7倍，Bmax增加了57％。放射自显影程序显示，当给予产生围绕MR的Kd浓度的示踪剂量的类固醇时，相同的IL1处理使海马所有锥体细胞层和齿状回中氚标记的内源性MR配体皮质酮的保留减少了40 - 60％。鉴于海马MR的亲和力降低，体内皮质酮保留的减少是可以预测的。这些数据与以下假设一致，即通过缺陷的海马MR导致的HPA轴反馈受损有助于在感染期间刺激肾上腺分泌皮质酮。
