Nagase H, Miyamasu M, Yamaguchi M, Kawasaki H, Ohta K, Yamamoto K, Morita Y, Hirai K
Department of Respiratory Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
J Allergy Clin Immunol. 2000 Dec;106(6):1132-9. doi: 10.1067/mai.2000.110923.
Chemokines play an important role in accumulation of eosinophils at allergic inflammatory sites. Systemic administration of glucocorticoids (GCCs) attenuates tissue eosinophilia. In vivo chemokine actions are regulated at levels of both ligand production and receptor expression. The inhibitory effects of GCCs on the production of eosinophil-active chemokines, such as eotaxin, have been well established. However, no data exist regarding the effects of GCCs on expression of chemokine receptors in eosinophils per se.
The objective of this study was to investigate the regulation of chemokine receptor expression in eosinophils by GCCs.
Chemokine receptor expression was analyzed by using flow cytometry and reverse transcriptase PCR. Intracellular Ca(2+) influx and chemotaxis were also analyzed.
Eosinophil CCR3 expression was slightly downregulated by 24-hour treatment with dexamethasone (DEX). On the other hand, DEX-treated eosinophils showed markedly increased CXCR4 expression ( approximately 6 fold) in a time- and dose-dependent fashion. In contrast to eosinophils, CXCR4 expression in neutrophils was only marginally affected by DEX. In DEX-treated eosinophils, stromal cell-derived factor 1alpha, a natural ligand for CXCR4, induced a higher level of Ca(2+) influx and chemotaxis compared with untreated cells.
GCCs upregulate the expression of CXCR4 in eosinophils but not in neutrophils. Because stromal cell-derived factor 1alpha may play a role in baseline trafficking of eosinophils into extravascular tissues rather than recruiting them directly to inflammatory sites, upregulation of CXCR4 by GCCs may mediate the antiallergic property of these drugs by sequestering eosinophils from the circulation to extravascular tissues.
趋化因子在嗜酸性粒细胞在过敏性炎症部位的积聚中起重要作用。全身应用糖皮质激素（GCCs）可减轻组织嗜酸性粒细胞增多。体内趋化因子的作用在配体产生和受体表达水平上均受到调节。GCCs对嗜酸性粒细胞活性趋化因子如嗜酸性粒细胞趋化因子产生的抑制作用已得到充分证实。然而，关于GCCs对嗜酸性粒细胞本身趋化因子受体表达的影响尚无相关数据。
本研究旨在探讨GCCs对嗜酸性粒细胞趋化因子受体表达的调节作用。
采用流式细胞术和逆转录聚合酶链反应分析趋化因子受体表达。同时分析细胞内钙离子内流和趋化性。
地塞米松（DEX）处理24小时可使嗜酸性粒细胞CCR3表达略有下调。另一方面，DEX处理的嗜酸性粒细胞CXCR4表达呈时间和剂量依赖性显著增加（约6倍）。与嗜酸性粒细胞不同，中性粒细胞CXCR4表达仅受到DEX的轻微影响。在DEX处理的嗜酸性粒细胞中，CXCR4的天然配体基质细胞衍生因子1α诱导的钙离子内流水平和趋化性高于未处理细胞。
GCCs上调嗜酸性粒细胞而非中性粒细胞CXCR4的表达。由于基质细胞衍生因子1α可能在嗜酸性粒细胞向血管外组织的基线转运中起作用，而非直接将它们招募到炎症部位，GCCs上调CXCR4可能通过将嗜酸性粒细胞从循环中隔离到血管外组织来介导这些药物的抗过敏特性。
