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Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes.

Forssmann U, Uguccioni M, Loetscher P, Dahinden CA, Langen H, Thelen M, Baggiolini M - J. Exp. Med. (1997)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Theodor Kocher Institute, University of Bern, CH-3000 Bern, Switzerland.

ABSTRACT
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.

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Cross-desensitization of human blood eosinophils. Fura2–loaded cells were stimulated sequentially at 90-s intervals with 50 nM  eotaxin-2 and another CC chemokine at the same concentration, and  [Ca2+]i dependent fluorescence changes were recorded. The tracings are  representative for three separate experiments performed under identical  conditions with cells from different donors.
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Figure 2: Cross-desensitization of human blood eosinophils. Fura2–loaded cells were stimulated sequentially at 90-s intervals with 50 nM eotaxin-2 and another CC chemokine at the same concentration, and [Ca2+]i dependent fluorescence changes were recorded. The tracings are representative for three separate experiments performed under identical conditions with cells from different donors.

Mentions: [Ca2+]i changes, were monitored in blood leukocytes after stimulation with 1 to 1,000 nM eotaxin-2. A marked, concentration-dependent effect was observed on eosinophils whereas neutrophils, monocytes and T lymphocytes did not respond. Desensitization experiments were then performed with eosinophils to gain information on receptor selectivity. As shown in Fig. 2, eosinophil stimulation with eotaxin-2 abrogated the response to eotaxin, attenuated the responses to MCP-3 and RANTES, but did not appreciably affect the response to MIP-1α. In agreement with these results the [Ca2+]i rise induced by eotaxin-2 was abrogated by prior stimulation with eotaxin, decreased by stimulation with RANTES or MCP-3, but was not affected by MIP-1α. Cross-desensititzation was also observed between eotaxin-2 and MCP-4 (data not shown). These results suggest that eotaxin-2 is a selective agonist for eosinophils. The complete cross-desensitization between eotaxin-2 and eotaxin indicates that both chemokines act mainly, if not exclusively, via CCR3. This conclusion is in agreement with the partial desensitization of the responses to RANTES and MCP-3, which are known to interact with at least two additional receptors, CCR1 and CCR2. The lack desensitization of the response to MIP-1α, on the other hand rules out an interaction of eotaxin-2 with CCR1.


Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes.

Forssmann U, Uguccioni M, Loetscher P, Dahinden CA, Langen H, Thelen M, Baggiolini M - J. Exp. Med. (1997)

Cross-desensitization of human blood eosinophils. Fura2–loaded cells were stimulated sequentially at 90-s intervals with 50 nM  eotaxin-2 and another CC chemokine at the same concentration, and  [Ca2+]i dependent fluorescence changes were recorded. The tracings are  representative for three separate experiments performed under identical  conditions with cells from different donors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196360&req=5

Figure 2: Cross-desensitization of human blood eosinophils. Fura2–loaded cells were stimulated sequentially at 90-s intervals with 50 nM eotaxin-2 and another CC chemokine at the same concentration, and [Ca2+]i dependent fluorescence changes were recorded. The tracings are representative for three separate experiments performed under identical conditions with cells from different donors.
Mentions: [Ca2+]i changes, were monitored in blood leukocytes after stimulation with 1 to 1,000 nM eotaxin-2. A marked, concentration-dependent effect was observed on eosinophils whereas neutrophils, monocytes and T lymphocytes did not respond. Desensitization experiments were then performed with eosinophils to gain information on receptor selectivity. As shown in Fig. 2, eosinophil stimulation with eotaxin-2 abrogated the response to eotaxin, attenuated the responses to MCP-3 and RANTES, but did not appreciably affect the response to MIP-1α. In agreement with these results the [Ca2+]i rise induced by eotaxin-2 was abrogated by prior stimulation with eotaxin, decreased by stimulation with RANTES or MCP-3, but was not affected by MIP-1α. Cross-desensititzation was also observed between eotaxin-2 and MCP-4 (data not shown). These results suggest that eotaxin-2 is a selective agonist for eosinophils. The complete cross-desensitization between eotaxin-2 and eotaxin indicates that both chemokines act mainly, if not exclusively, via CCR3. This conclusion is in agreement with the partial desensitization of the responses to RANTES and MCP-3, which are known to interact with at least two additional receptors, CCR1 and CCR2. The lack desensitization of the response to MIP-1α, on the other hand rules out an interaction of eotaxin-2 with CCR1.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Theodor Kocher Institute, University of Bern, CH-3000 Bern, Switzerland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus