Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils.
BACKGROUND
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.


OBJECTIVE
The objective of this study was to investigate the regulation of chemokine receptor expression in eosinophils by GCCs.


METHODS
Chemokine receptor expression was analyzed by using flow cytometry and reverse transcriptase PCR. Intracellular Ca(2+) influx and chemotaxis were also analyzed.


RESULTS
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.


CONCLUSIONS
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.
Nagase
H
H
Department of Respiratory Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Miyamasu
M
M
Yamaguchi
M
M
Kawasaki
H
H
Ohta
K
K
Yamamoto
K
K
Morita
Y
Y
Hirai
K
K
D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000737:chemistry* / Q000166:cytology / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D019718:Receptors, CXCR4 / Q000097:blood*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D005938:Glucocorticoids; D019718:Receptors, CXCR4; D003907:Dexamethasone