Up-regulation of CCR1 and CCR3 and induction of chemotaxis to CC chemokines by IFN-gamma in human neutrophils.
Human neutrophils (polymorphonuclear leukocytes; PMN) respond to some CXC chemokines but do not migrate to CC chemokines. Recent work has shown that chemokine receptors can be modulated by inflammatory cytokines. In this study, the effect of IFN-gamma, a prototypic Th1 cytokine, on chemokine receptor expression in PMN was investigated. IFN-gamma caused a rapid (approximately 1 h) and concentration-dependent increase of CCR1 and CCR3 mRNA. The expression of CCR2, CCR5, and CXCR1-4 was not augmented. IFN-gamma-treated PMN, but not control cells, expressed specific binding sites for labeled monocyte-chemotactic protein (MCP)-3 and migrated to macrophage-inflammatory protein (MIP)-1alpha, RANTES, MCP-3, MIP-5/HCC2, and eotaxin. 7B11, a mAb for CCR3, inhibited the chemotactic response of IFN-gamma-treated PMN to eotaxin, and aminoxypentane-RANTES blocked PMN migration to RANTES. These results suggest that the selectivity of certain chemokines for their target cells may be altered by cytokines produced within an inflammatory context. Since PMN may play a role in orienting immunity toward Th1 responses, it is possible to speculate that IFN-gamma not only promotes Th1 differentiation directly, but also reorients the functional significance of Th2 effector cytokines by broadening the spectrum of their action to include PMN.
Bonecchi
R
R
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Polentarutti
N
N
Luini
W
W
Borsatti
A
A
Bernasconi
S
S
Locati
M
M
Power
C
C
Proudfoot
A
A
Wells
T N
TN
Mackay
C
C
Mantovani
A
A
Sozzani
S
S
D015703:Antigens, CD / Q000235:genetics; D054410:Chemokine CCL7; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D016207:Cytokines; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000502:physiology*; D016209:Interleukin-8 / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D015854:Up-Regulation / Q000276:immunology*
D015703:Antigens, CD; C515450:CCL7 protein, human; C515300:CCR1 protein, human; C515350:CCR3 protein, human; D054410:Chemokine CCL7; D016207:Cytokines; D016209:Interleukin-8; D018945:Monocyte Chemoattractant Proteins; D012333:RNA, Messenger; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D007371:Interferon-gamma