Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3.
The CC chemokine eotaxin is a selective chemoattractant for guinea pig eosinophils, first purified from bronchoalveolar lavage fluid in a guinea pig model of allergic airway inflammation. We have now isolated the gene and cDNA for a human counterpart of eotaxin. The gene maps to chromosome 17 and is expressed constitutively at high levels in small intestine and colon, and at lower levels in various other tissues. The deduced mature protein sequence is 66% identical to human monocyte chemoattractant protein-1, and 60% identical to guinea pig eotaxin. Recombinant human eotaxin produced in insect cells induced a calcium flux response in normal human eosinophils, but not in neutrophils or monocytes. The response could not be desensitized by pretreatment of eosinophils with other CC chemokines, suggesting a unique receptor. In this regard, we show that human eotaxin is a potent and highly specific agonist for CC chemokine receptor 3, a G protein-coupled receptor selectively expressed in human eosinophils. Thus eotaxin and CC chemokine receptor 3 may be host factors highly specialized for eosinophil recruitment in inflammation, and may be good targets for the development of selective drugs for inflammatory diseases where eosinophils contribute to pathogenesis, such as asthma.
Kitaura
M
M
Shionogi Institute for Medical Science, Osaka, Japan.
Nakajima
T
T
Imai
T
T
Harada
S
S
Combadiere
C
C
Tiffany
H L
HL
Murphy
P M
PM
Yoshie
O
O
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000097:blood; D054413:Chemokine CCL11; D018925:Chemokines / Q000737:chemistry / Q000494:pharmacology; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000096:biosynthesis / Q000235:genetics; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics* / Q000494:pharmacology; D017931:DNA Primers; D018076:DNA, Complementary; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid
C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D017931:DNA Primers; D018076:DNA, Complementary; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; D019204:GTP-Binding Proteins; D002118:Calcium