Ruiz P, Gomez F, King M, Lopez R, Darby C, Schreiber A D
Hematology-Oncology Section, University of Pennsylvania Cancer Center, Philadelphia 19104.
J Clin Invest. 1991 Jul;88(1):149-57. doi: 10.1172/JCI115271.
Although glucocorticoids are widely used in the treatment of immunohematologic disease, their relative efficacy is uncertain. We used an animal model, which has helped to elucidate the role of splenic macrophage Fc gamma receptors in the clearance of IgG-coated cells, to investigate whether each Fc gamma receptor is modulated by glucocorticoids to the same extent and to examine the relative potency of three commonly used glucocorticoids. Cortisol, prednisone, and dexamethasone all impaired the clearance of IgG-coated erythrocytes. However, dexamethasone was more effective than either prednisone or cortisol (P less than 0.001). Furthermore, splenic macrophages isolated from glucocorticoid-treated animals expressed impaired Fc gamma receptor function. This effect was greater in macrophages isolated from dexamethasone-treated animals, as compared to either cortisol- or prednisone-treated animals (P less than 0.001). To assess the effect of glucocorticoids on the two types of guinea pig splenic macrophage Fc gamma receptors, Fc gamma R1,2 and Fc gamma R2, specific immunoglobulin isotypes were used to measure macrophage binding of IgG-sensitized erythrocytes. Cortisol and prednisone primarily affected Fc gamma R2, whereas dexamethasone inhibited the function of both guinea pig Fc gamma receptors. Furthermore, dexamethasone was more effective (P less than 0.01) than either prednisone or cortisol in inhibiting the ability of both receptors to bind IgG-sensitized cells. Fluorescence-activated cell sorter analysis and fluorescence microscopy with monoclonal antibodies specific for each of these two receptors demonstrated that essentially all splenic macrophages expressed both receptors, and that these glucocorticoids decreased the level of each Fc gamma receptor protein expressed, rather than altering receptor mobility and clustering in the macrophage membrane. The effect on both Fc gamma receptors was greatest with dexamethasone and least with cortisol. These studies demonstrate the significant role of guinea pig splenic macrophage Fc gamma R2 in immune clearance and in the binding of IgG-coated cells. They demonstrate a differential effect of glucocorticoid hormones on Fc gamma receptor function and on surface receptor protein. Furthermore, they suggest that dexamethasone may be a more effective glucocorticoid than either prednisone or cortisol in inhibiting the clearance of IgG-coated cells by its effect on splenic macrophage Fc gamma receptors.
尽管糖皮质激素广泛用于免疫血液学疾病的治疗，但其相对疗效尚不确定。我们使用了一种动物模型（该模型有助于阐明脾巨噬细胞Fcγ受体在IgG包被细胞清除中的作用）来研究每种Fcγ受体是否受到糖皮质激素同等程度的调节，并检验三种常用糖皮质激素的相对效力。皮质醇、泼尼松和地塞米松均损害了IgG包被红细胞的清除。然而，地塞米松比泼尼松或皮质醇更有效（P<0.001）。此外，从糖皮质激素处理的动物分离出的脾巨噬细胞表达受损的Fcγ受体功能。与皮质醇或泼尼松处理的动物相比，从地塞米松处理的动物分离出的巨噬细胞这种效应更大（P<0.001）。为评估糖皮质激素对豚鼠脾巨噬细胞两种类型的Fcγ受体（FcγR1,2和FcγR2）的影响，使用特异性免疫球蛋白同种型来测量巨噬细胞对IgG致敏红细胞的结合。皮质醇和泼尼松主要影响FcγR2，而地塞米松抑制两种豚鼠Fcγ受体的功能。此外，地塞米松在抑制两种受体结合IgG致敏细胞的能力方面比泼尼松或皮质醇更有效（P<0.01）。荧光激活细胞分选分析以及使用针对这两种受体各自的单克隆抗体的荧光显微镜检查表明，基本上所有脾巨噬细胞都表达这两种受体，并且这些糖皮质激素降低了每种Fcγ受体蛋白的表达水平，而不是改变受体在巨噬细胞膜中的流动性和聚集。地塞米松对两种Fcγ受体的作用最大，皮质醇最小。这些研究证明了豚鼠脾巨噬细胞FcγR2在免疫清除以及IgG包被细胞结合中的重要作用。它们证明了糖皮质激素对Fcγ受体功能和表面受体蛋白的不同作用。此外，它们表明地塞米松通过其对脾巨噬细胞Fcγ受体的作用，在抑制IgG包被细胞的清除方面可能比泼尼松或皮质醇更有效。
