Wiegers G J, Stec I E, Klinkert W E, Linthorst A C, Reul J M
Max Planck Institute of Psychiatry, Section of Neuropsychopharmacology, Munich, Germany.
Neuroendocrinology. 2001 Feb;73(2):139-48. doi: 10.1159/000054630.
Glucocorticoids inhibit stimulus-induced T-cell proliferation, an early and essential parameter of cellular immunity. It was recently found however that physiological concentrations of glucocorticoids can also accelerate, not only inhibit, rat T-cell mitogenesis. We investigated mechanism(s) underlying mitogenic actions of glucocorticoids on anti-T-cell receptor (TCR)- and concanavalin A (Con A)-induced T-cell proliferation. Surprisingly, the ability of the glucocorticoid corticosterone (CORT) to either enhance or inhibit T-cell proliferation was found to depend primarily on the cell density and the timing of the cultures. At cell densities up to 1 x 10(5) cells/well (i.e. 'low' density), CORT inhibited T-cell proliferation irrespective of the culture time. In contrast, at cell densities of 2 x 10(5) cells/well and higher ('high' density), CORT potently stimulated T-cell mitogenesis during the first 2-3 culture days, but subsequently inhibited the proliferative response after 5-7 days. The glucocorticoid receptor antagonist RU486 completely abolished the effects of CORT. However, production of the main T cell growth factor interleukin (IL)-2 was inhibited by CORT at both 'low' and 'high' cell densities. In addition, irrespective of cell density, T-cell mitogenesis under either control conditions or in presence of CORT was completely blocked by an anti-IL-2-receptor-alpha-chain (IL-2Ralpha) antibody, indicating that T-cell proliferation was dependent on the IL-2 pathway. Immunofluorescence staining of IL-2Ralpha on CD4+ cells after 2-3 days in culture was increased by CORT, but only on cells cultured at 'high' density. Thus, glucocorticoids increase T-cell responsiveness to IL-2 under conditions of 'high' cell density only. We conclude that glucocorticoids may contribute to a more efficient early stage of cellular immune responses under conditions of intimate cell-to-cell contact (i.e. 'high' cell density), a situation likely to be present in vivo, for instance in lymph nodes. Thus, these findings are relevant to our understanding of the glucocorticoid control of immune function.
糖皮质激素可抑制刺激诱导的T细胞增殖，这是细胞免疫的一个早期且关键的参数。然而最近发现，生理浓度的糖皮质激素不仅能抑制，还能加速大鼠T细胞的有丝分裂。我们研究了糖皮质激素对抗T细胞受体（TCR）和刀豆蛋白A（Con A）诱导的T细胞增殖的促有丝分裂作用的潜在机制。令人惊讶的是，发现糖皮质激素皮质酮（CORT）增强或抑制T细胞增殖的能力主要取决于细胞密度和培养时间。在细胞密度高达1×10⁵个细胞/孔（即“低”密度）时，无论培养时间如何，CORT均抑制T细胞增殖。相反，在细胞密度为2×10⁵个细胞/孔及更高（“高”密度）时，CORT在前2 - 3个培养日强烈刺激T细胞有丝分裂，但在5 - 7天后抑制增殖反应。糖皮质激素受体拮抗剂RU486完全消除了CORT的作用。然而，在“低”和“高”细胞密度下，主要的T细胞生长因子白细胞介素（IL）-2的产生均受到CORT的抑制。此外，无论细胞密度如何，抗IL - 2受体α链（IL - 2Rα）抗体均可完全阻断对照条件下或存在CORT时的T细胞有丝分裂，表明T细胞增殖依赖于IL - 2途径。培养2 - 3天后，CORT可增加CD4⁺细胞上IL - 2Rα的免疫荧光染色，但仅在“高”密度培养的细胞上。因此，糖皮质激素仅在“高”细胞密度条件下增加T细胞对IL - 2的反应性。我们得出结论，在细胞间紧密接触（即“高”细胞密度）的条件下，糖皮质激素可能有助于细胞免疫反应更高效的早期阶段，这种情况在体内可能存在，例如在淋巴结中。因此，这些发现与我们对糖皮质激素免疫功能控制的理解相关。
