Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils.
The CC chemokine eotaxin, identified in guinea pigs and also recently in mice, may be a key element for the selective recruitment of eosinophils to certain inflamed tissues. Using a partial mouse eotaxin CDNA probe, the human eotaxin gene was cloned and found to be 61.8 and 63.2% identical at the amino acid level to guinea pig and mouse eotaxin. Human eotaxin protein was a strong and specific eosinophil chemoattractant in vitro and was an effective eosinophil chemoattractant when injected into the skin of a rhesus monkey. Radiolabeled eotaxin was used to identify a high affinity receptor on eosinophils (0.52 nM Kd), expressed at 4.8 x 10(4) sites per cell. This receptor also bound RANTES and monocyte chemotactic protein-3 with lower affinity, but not macrophage inflammatory protein-1 alpha. Eotaxin could desensitize calcium responses of eosinophils to RANTES and monocyte chemotactic protein-3, although RANTES was able to only partially desensitize eosinophil calcium responses to eotaxin. Immunohistochemistry on human nasal polyp with antieotaxin mAbs showed that certain leukocytes as well as respiratory epithelium were intensely immunoreactive, and eosinophil infiltration occurred at sites of eotaxin upregulation. Thus eotaxin in humans is a potent and selective eosinophil chemoattractant that is expressed by a variety cell types in certain inflammatory conditions.
Ponath
P D
PD
LeukoSite, Inc., Cambridge, Massachusetts 02142, USA.
Qin
S
S
Ringler
D J
DJ
Clark-Lewis
I
I
Wang
J
J
Kassam
N
N
Smith
H
H
Shi
X
X
Gonzalo
J A
JA
Newman
W
W
Gutierrez-Ramos
J C
JC
Mackay
C R
CR
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000378:metabolism; D054410:Chemokine CCL7; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003001:Cloning, Molecular; D016207:Cytokines / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D011485:Protein Binding; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; C515456:CCL11 protein, human; C515450:CCL7 protein, human; C515350:CCR3 protein, human; C515457:Ccl11 protein, mouse; C515451:Ccl7 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D018076:DNA, Complementary; D018945:Monocyte Chemoattractant Proteins; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D002118:Calcium