Glucocorticoids inhibit cytokine-mediated eosinophil survival.
Glucocorticoids inhibit cytokine-mediated eosinophil survival.
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DOI：
10.4049/jimmunol.147.10.3490
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发表时间：
1991-11
影响因子：
4.4
通讯作者：
N. Wallen;H. Kita;D. Weiler;G. Gleich
中科院分区：
文献类型：
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作者：
N. Wallen;H. Kita;D. Weiler;G. Gleich
糖皮质激素的特征是在体内诱导嗜酸性粒细胞减少，并且可有效治疗过敏性和其他嗜酸性粒细胞疾病。我们在体外研究了糖皮质激素对细胞因子诱导的人嗜酸性粒细胞存活的影响。通过 Percoll 密度梯度从正常或轻度特应性志愿者中纯化嗜酸性粒细胞，并在细胞因子加类固醇存在下孵育 4 天。通过用荧光素二乙酸酯和碘化丙啶对细胞染色来测定细胞活力。在没有糖皮质激素的情况下，人 rIL-5 以剂量依赖性方式增强嗜酸性粒细胞的存活，从最小作用的 22 fM 到最大作用的 2200 fM。当用次最大浓度的 rIL-5 (220 fM) 培养嗜酸性粒细胞时，地塞米松、甲泼尼龙和氢化可的松以剂量依赖性方式抑制嗜酸性粒细胞的存活。抑制作用具有时间依赖性，需要嗜酸性粒细胞接触地塞米松至少 2 天。 1000 nM 的地塞米松、甲泼尼龙和氢化可的松可抑制 88 +/- 2%、66 +/- 9% 和 37 +/- 7% 的存活率。相比之下，雌二醇和睾酮（1000 nM）对嗜酸性粒细胞的存活没有影响。当嗜酸性粒细胞与不同浓度的人 rIL-5 和 1000 nM 地塞米松一起孵育时，在较高浓度的人 rIL-5 下存活抑制降低，并被 23,000 fM 人 rIL-5 完全消除。人重组粒细胞-巨噬细胞 CSF、人 rIL-3 和人 rIFN-γ 也以剂量依赖性方式增强嗜酸性粒细胞存活，并且当使用这些细胞因子的次最大浓度时，地塞米松 (1000 nM) 强烈抑制细胞存活。地塞米松的作用可被较高浓度的粒细胞-巨噬细胞 CSF (10 U/ml) 和 IL-3 (3 ng/ml) 逆转。然而，即使1000 U/ml IFN-γ也不能克服地塞米松的抑制作用，表明IFN-γ和其他细胞因子诱导的嗜酸性粒细胞存活的机制存在差异。这些结果表明，糖皮质激素对嗜酸性粒细胞的存活具有直接的抑制作用，这对于治疗过敏性和其他嗜酸性粒细胞疾病可能很重要。较高量的细胞因子对这种作用的拮抗可能是糖皮质激素抵抗的机制。
Glucocorticoids characteristically induce eosinopenia in vivo and are effective for treating allergic and other eosinophilic disorders. We studied the effect of glucocorticoids on cytokine-induced survival of human eosinophils in vitro. Eosinophils were purified from normal or mildly atopic volunteers by Percoll density gradient and incubated for 4 days in the presence of cytokine plus steroid. Cell viabilities were determined by staining cells with fluorescein diacetate and propidium iodide. In the absence of glucocorticoids, human rIL-5 enhanced eosinophil survival in a dose-dependent manner, from 22 fM for a minimal effect to 2200 fM for maximal effect. When eosinophils were cultured with a submaximal concentration of rIL-5 (220 fM), dexamethasone, methylprednisolone, and hydrocortisone inhibited eosinophil survival in a dose-dependent manner. Inhibition was time-dependent and required at least 2 days' exposure of eosinophils to dexamethasone. Dexamethasone, methylprednisolone, and hydrocortisone at 1000 nM inhibited survival by 88 +/- 2, 66 +/- 9 and 37 +/- 7%. In contrast, estradiol and testosterone (1000 nM) had no effect on eosinophil survival. When eosinophils were incubated with varying concentrations of human rIL-5 and 1000 nM dexamethasone, survival inhibition was reduced at higher concentrations of human rIL-5, and completely abolished by human rIL-5 23,000 fM. Human recombinant granulocyte-macrophage CSF, human rIL-3, and human rIFN-gamma also enhanced eosinophil survival in a dose-dependent manner and dexamethasone (1000 nM) strongly inhibited cell survival when submaximal concentrations of these cytokines were used. The effects of dexamethasone were reversed by higher concentrations of granulocyte-macrophage CSF (10 U/ml) and IL-3 (3 ng/ml). However, even 1000 U/ml IFN-gamma did not overcome dexamethasone inhibition, indicating a difference between the mechanism of eosinophil survival induced by IFN-gamma and other cytokines. These results suggest that glucocorticoids exert a direct, inhibitory effect on eosinophil survival, which may be important in the treatment of allergic and other eosinophilic disorders. Antagonism of this effect by higher amounts of cytokine may be a mechanism for glucocorticoid resistance.