Dennis G, June C H, Mizuguchi J, Ohara J, Witherspoon K, Finkelman F D, McMillan V, Mond J J
Department of Medicine, Walter Reed Army Medical Center, Washington, DC 20014.
J Immunol. 1987 Oct 15;139(8):2516-23.
Glucocorticoids have been shown to play a major role in influencing the activation of B lymphocytes. In view of our recent observation that dexamethasone exerts a marked suppressive effect on an early event in B cell activation that is stimulated by anti-Ig antibody, we investigated its activity on other stimuli that induce intracellular events similar to those produced by anti-Ig antibody. Because the intracellular events that occur after B cell stimulation with phorbol myristate acetate and the calcium ionophore A23187 appear to mimic those that occur after B cell stimulation with anti-Ig antibody, we studied whether the cellular responses elicited by these activation stimuli are affected in a similar fashion by dexamethasone. Whereas anti-Ig antibody-stimulated entry of G0 B cells to the G1 and S phase of the cell cycle was markedly suppressed by dexamethasone, phorbol myristate acetate/A23187 stimulation of these events was resistant to dexamethasone. Our finding that anti-Ig-induced cross-linking of B cell surface Ig, as measured by surface Ig capping, was not inhibited by dexamethasone suggested that corticosteroids inhibit anti-Ig-induced B cell proliferation at a step distal to membrane Ig cross-linking and proximal to phosphatidylinositol bisphosphate hydrolysis. This hypothesis is supported by experiments presented in this manuscript which demonstrate that dexamethasone inhibits anti-Ig-stimulated phosphatidylinositol bisphosphate hydrolysis. We also found that dexamethasone markedly inhibited anti-Ig antibody-stimulated increases in intracellular ionized calcium concentrations. This dexamethasone-mediated suppression is time-dependent as it is not seen when B cells are cultured with dexamethasone for less than 6 hr. Our data suggest that the immunomodulatory activity of glucocorticoids is exerted by binding to its nuclear receptor, thereby preventing the generation of second messengers required for cell activation after agonist-receptor interaction.
糖皮质激素已被证明在影响B淋巴细胞的激活中起主要作用。鉴于我们最近观察到地塞米松对由抗Ig抗体刺激的B细胞激活的早期事件具有显著的抑制作用，我们研究了其对其他诱导与抗Ig抗体产生的细胞内事件相似的刺激的活性。由于用佛波酯肉豆蔻酸酯和钙离子载体A23187刺激B细胞后发生的细胞内事件似乎模拟了用抗Ig抗体刺激B细胞后发生的事件，我们研究了这些激活刺激引发的细胞反应是否受到地塞米松类似方式的影响。虽然地塞米松显著抑制抗Ig抗体刺激的G0 B细胞进入细胞周期的G1和S期，但佛波酯肉豆蔻酸酯/A23187对这些事件的刺激对地塞米松具有抗性。我们的发现表明，用地塞米松测量的抗Ig诱导的B细胞表面Ig交联（通过表面Ig帽化测量）不受抑制，这表明皮质类固醇在膜Ig交联远端和磷脂酰肌醇二磷酸水解近端的步骤中抑制抗Ig诱导的B细胞增殖。本手稿中提出的实验支持了这一假设，这些实验表明地塞米松抑制抗Ig刺激的磷脂酰肌醇二磷酸水解。我们还发现地塞米松显著抑制抗Ig抗体刺激的细胞内游离钙浓度的增加。这种地塞米松介导的抑制是时间依赖性的，因为当B细胞用地塞米松培养少于6小时时未见这种抑制。我们的数据表明，糖皮质激素的免疫调节活性是通过与其核受体结合来发挥作用的，从而阻止激动剂-受体相互作用后细胞激活所需的第二信使的产生。
