Expression of CXCR4 in eosinophils: functional analyses and cytokine-mediated regulation.
We examined the expression of transcripts of a panel of chemokine receptors in human eosinophils and found intense constitutive expression of CXCR4 mRNA. Although surface CXCR4 protein was hardly detectable in the peripheral blood or freshly isolated eosinophils, surface expression of CXCR4 became gradually apparent during incubation at 37 degrees C. In contrast, the level of CCR3 expression was virtually unchanged during the incubation. Stromal cell-derived factor-1alpha (SDF-1alpha), the natural ligand of CXCR4, elicited an apparent Ca2+ influx in these cells and induced a strong migratory response comparable to that by eotaxin. The surface expression of CXCR4 in eosinophils was up-regulated by IFN-gamma, TNF-alpha, and TGF-beta while it was down-regulated by IL-4 and eosinophil-directed hemopoietins such as IL-5. The CXCR4 expression did not always parallel the apoptotic changes in cytokine-treated eosinophils. In contrast to IL-4 and IFN-gamma, IL-5 potently reduced the level of CXCR4 mRNA. It seems unlikely that CXCR4 is fundamentally involved in the pathogenesis of allergic disorders by inducing the migration of eosinophils toward inflammatory sites, because a Th2-dominant state down-regulates eosinophil CXCR4 expression. However, CXCR4 may affect the size of the mobilizable pool by holding eosinophils at noninflamed tissues. Th2-dominant state may favor the liberation of eosinophils by down-regulating CXCR4 expression. The interplay between CXCR4 and SDF-1alpha in eosinophils potentially plays an important role in the accumulation of these cells at the allergic inflammatory sites.
Nagase
H
H
Departments of Respiratory Medicine, Allergy and Rheumatology, and Bioregulatory Function, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Miyamasu
M
M
Yamaguchi
M
M
Fujisawa
T
T
Ohta
K
K
Yamamoto
K
K
Morita
Y
Y
Hirai
K
K
D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D054413:Chemokine CCL11; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D004804:Eosinophils / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis; D054397:Receptors, CCR3; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D017154:Stromal Cells / Q000502:physiology
C515456:CCL11 protein, human; C515350:CCR3 protein, human; C515255:CXCL12 protein, human; D054413:Chemokine CCL11; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D016207:Cytokines; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine