Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes.
A novel human CC chemokine consisting of 78 amino acids and having a molecular mass of 8,778.3 daltons (VVIPSPCCMF FVSKRIPENR VVSYQLSSRS TCLKAGVIFT TKKGQQ SCGD PKQEWVQRYM KNLDAKQKKA SPRARAVA) was isolated together with three minor COOH-terminally truncated variants with 73, 75, and 76 residues. The new chemokine was termed eotaxin-2 because it is functionally very similar to eotaxin. In terms of structure, however, eotaxin and eotaxin-2 are rather distant, they share only 39% identical amino acids and differ almost completely in the NH2-terminal region. Eotaxin-2 induced chemotaxis of eosinophils as well as basophils, with a typically bimodal concentration dependence, and the release of histamine and leukotriene C4 from basophils that had been primed with IL-3. In all assays, eotaxin-2 had the same efficacy as eotaxin, but was somewhat less potent. The migration and the release responses were abrogated in the presence of a monoclonal antibody that selectively blocks the eotaxin receptor, CCR3, indicating that eotaxin-2, like eotaxin, acts exclusively via CCR3. Receptor usage was also studied in desensitization experiments by measuring [Ca2+]i changes in eosinophils. Complete cross-desensitization was observed between eotaxin-2, eotaxin and MCP-4 confirming activation via CCR3. No Ca2+ mobilization was obtained in neutrophils, monocytes and lymphocytes, in agreement with the lack of chemotactic responsiveness. Intradermal injection of eotaxin-2 in a rhesus monkey (100 or 1,000 pmol per site) induced a marked local infiltration of eosinophils, which was most pronounced in the vicinity of postcapillary venules and was comparable to the effect of eotaxin.
Forssmann
U
U
Theodor Kocher Institute, University of Bern, CH-3000 Bern, Switzerland.
Uguccioni
M
M
Loetscher
P
P
Dahinden
C A
CA
Langen
H
H
Thelen
M
M
Baggiolini
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001491:Basophils / Q000187:drug effects*; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil / Q000494:pharmacology*; D002633:Chemotaxis; D016207:Cytokines / Q000737:chemistry / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000502:physiology*
C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D017997:Leukotriene C4