Lamas A M, Leon O G, Schleimer R P
University of Miami School of Medicine, Department of Medicine, FL 33101.
J Immunol. 1991 Jul 1;147(1):254-9.
The role of the eosinophil as an active proinflammatory cell in asthma and other allergic disorders has been well established. Glucocorticosteroids have long been used therapeutically as antiinflammatory agents in a variety of disease states where eosinophilia is a prominent feature. Although glucocorticoids are known to reduce tissue and circulating eosinophil numbers, the mechanisms by which they do so have not been clearly elucidated. Culture of eosinophils in vascular endothelial cell supernatants (VEC SUP) induces phenotypic and functional changes and prolongs the survival of the eosinophils. The survival-promoting activity in VEC SUP was shown to be granulocyte-macrophage CSF (GM-CSF) by neutralization with specific antibody. The potent glucocorticosteroid, dexamethasone (DEX), inhibited the prolongation of eosinophil survival caused by culture in either VEC SUP or human rGM-CSF. DEX (10(-6) M) exerted a direct survival-inhibitory effect on the eosinophil by the 4th day in culture in VEC SUP. This survival-inhibitory effect was dependent on the concentration of DEX (10(-10)-10(-6) M). Other glucocorticoids, including prednisolone (10(-7), 10(-6) M) and hydrocortisone (10(-7), 10(-6) M) also inhibited survival. The rank order of potency of the steroids indicates that this effect is mediated by a glucocorticoid receptor. This conclusion is supported by the failure of the sex steroids testosterone (10(-8)-10(-6) M) or beta-estradiol (10(-6) M) to inhibit eosinophil survival in the presence of VEC SUP. The effect of glucocorticoids on eosinophils is not a simple direct toxic effect because it was reversed by higher concentrations of GM-CSF. DEX shifted the GM-CSF dose-response curve for survival approximately fivefold to the right. GM-CSF induced a shift in eosinophil buoyant density which was partially blocked by DEX. These results suggest that glucocorticoids may inhibit elements of cytokine "priming" of eosinophils and that the eosinophilopenic effects of glucocorticoids may result in part from a direct effect on the eosinophil within a regulatory system involving cytokines.
嗜酸性粒细胞作为哮喘和其他过敏性疾病中一种活跃的促炎细胞，其作用已得到充分证实。长期以来，糖皮质激素在嗜酸性粒细胞增多为突出特征的多种疾病状态下，一直作为抗炎药物用于治疗。虽然已知糖皮质激素可减少组织和循环中的嗜酸性粒细胞数量，但其作用机制尚未完全阐明。嗜酸性粒细胞在血管内皮细胞上清液（VEC SUP）中培养会诱导其表型和功能发生变化，并延长其存活时间。用特异性抗体中和后表明，VEC SUP中的存活促进活性是粒细胞巨噬细胞集落刺激因子（GM-CSF）。强效糖皮质激素地塞米松（DEX）可抑制在VEC SUP或人重组GM-CSF中培养所致的嗜酸性粒细胞存活时间延长。在VEC SUP中培养至第4天时，DEX（10⁻⁶ M）对嗜酸性粒细胞产生直接的存活抑制作用。这种存活抑制作用取决于DEX的浓度（10⁻¹⁰ - 10⁻⁶ M）。其他糖皮质激素，包括泼尼松龙（10⁻⁷、10⁻⁶ M）和氢化可的松（10⁻⁷、10⁻⁶ M）也抑制存活。这些类固醇的效力顺序表明这种作用是由糖皮质激素受体介导的。在存在VEC SUP的情况下，性类固醇睾酮（10⁻⁸ - 10⁻⁶ M）或β-雌二醇（10⁻⁶ M）未能抑制嗜酸性粒细胞存活，这支持了这一结论。糖皮质激素对嗜酸性粒细胞的作用并非简单的直接毒性作用，因为较高浓度的GM-CSF可逆转这种作用。DEX使GM-CSF的存活剂量反应曲线向右移动约五倍。GM-CSF诱导嗜酸性粒细胞浮力密度发生变化，而DEX可部分阻断这种变化。这些结果表明，糖皮质激素可能抑制嗜酸性粒细胞细胞因子“启动”的某些环节，且糖皮质激素的嗜酸性粒细胞减少作用可能部分源于在涉及细胞因子的调节系统内对嗜酸性粒细胞的直接作用。
