Wiegers G J, Reul J M, Holsboer F, de Kloet E R
Max-Planck Institute of Psychiatry, Department of Neuroendocrinology, Munich, Germany.
Endocrinology. 1994 Dec;135(6):2351-7. doi: 10.1210/endo.135.6.7988417.
Numerous previous studies investigating the effects of corticosteroids on immune proliferation reported almost unanimously inhibitory effects. However, in many of these studies, high concentrations of corticosteroids (micromolar range) and long incubation times (days) were used. We have investigated whether corticosteroid hormones at low physiological (nanomolar) vs. high (micromolar) concentrations have distinct effects on immune cells after short term (minutes) as opposed to long term preexposure (hours). When rat splenocytes were preincubated with high concentrations (0.1-1 microM) of corticosterone (CORT) or with the specific glucocorticoid agonist RU 28362 (0.1 microM) for 1-6 h, washed, and then exposed to the T-cell mitogen Concanavalin-A, a time- and dose-dependent inhibition of lymphocyte mitogenesis over the next 3 days of culture was found. Preincubation with the glucocorticoid antagonist RU 486 completely blocked this inhibitory effect of CORT and RU 28362. Preexposure of splenocytes to CORT for 10-60 min did not alter mitogenesis. No differences were observed between intact and adrenalectomized (ADX) rats. However, if splenocytes from ADX rats were used in the presence of the glucocorticoid antagonist RU 486, the proliferative response over a 3-day period was stimulated by short term preexposure (10-30 min) to low concentrations (3-30 nM) of CORT. Under these incubation conditions, the mineralocorticoid aldosterone, in the presence of RU 486; also produced a stimulatory effect on ADX splenic lymphocyte mitogenesis, whereas RU 28362 was not effective. Corticosteroid receptor binding studies revealed the presence of mineralocorticoid (MR) as well as glucocorticoid (GR) receptors (45 and 600 fmol/mg protein, respectively) in the spleen. In conclusion, low physiological concentrations of CORT and aldosterone have novel stimulatory properties on mitogenesis of splenic lymphocytes from ADX rats. These effects become evident in the presence of GR antagonist and persist after short corticosteroid preexposure times. In contrast, after prolonged preincubation with high concentrations of corticosteroids, the well known immunosuppressive action is observed. We postulate that distinct MR- and GR-mediated effects may underlie these differential steroid actions on splenic lymphocyte proliferation.
以往众多研究探讨了皮质类固醇对免疫增殖的影响，几乎一致报道了其抑制作用。然而，在许多这些研究中，使用的是高浓度的皮质类固醇（微摩尔范围）和较长的孵育时间（数天）。我们研究了低生理浓度（纳摩尔）与高浓度（微摩尔）的皮质类固醇激素在短期（数分钟）与长期预暴露（数小时）后对免疫细胞是否有不同影响。当大鼠脾细胞用高浓度（0.1 - 1微摩尔）的皮质酮（CORT）或特异性糖皮质激素激动剂RU 28362（0.1微摩尔）预孵育1 - 6小时，洗涤后，再暴露于T细胞丝裂原刀豆球蛋白A时，发现在接下来3天的培养中淋巴细胞有丝分裂呈时间和剂量依赖性抑制。用糖皮质激素拮抗剂RU 486预孵育可完全阻断CORT和RU 28362的这种抑制作用。脾细胞预暴露于CORT 10 - 60分钟不会改变有丝分裂。完整大鼠和肾上腺切除（ADX）大鼠之间未观察到差异。然而，如果在糖皮质激素拮抗剂RU 486存在的情况下使用ADX大鼠的脾细胞，短期预暴露（10 - 30分钟）于低浓度（3 - 30纳摩尔）的CORT可刺激3天内的增殖反应。在这些孵育条件下，盐皮质激素醛固酮在RU 486存在时，也对ADX脾淋巴细胞有丝分裂产生刺激作用，而RU 28362无效。皮质类固醇受体结合研究显示脾中存在盐皮质激素（MR）以及糖皮质激素（GR）受体（分别为45和600飞摩尔/毫克蛋白）。总之，低生理浓度的CORT和醛固酮对ADX大鼠脾淋巴细胞的有丝分裂具有新的刺激特性。这些作用在GR拮抗剂存在时变得明显，并在短期皮质类固醇预暴露后持续存在。相反，在高浓度皮质类固醇长时间预孵育后，会观察到众所周知的免疫抑制作用。我们推测不同的MR和GR介导的作用可能是这些类固醇对脾淋巴细胞增殖产生不同作用的基础。
