Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Sep 1;100(5):1137–1143. doi: 10.1172/JCI119624

High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines.

M Uguccioni 1, C R Mackay 1, B Ochensberger 1, P Loetscher 1, S Rhis 1, G J LaRosa 1, P Rao 1, P D Ponath 1, M Baggiolini 1, C A Dahinden 1
PMCID: PMC508288  PMID: 9276730

Abstract

Eosinophil leukocytes express high numbers of the chemokine receptor CCR3 which binds eotaxin, monocyte chemotactic protein (MCP)-4, and some other CC chemokines. In this paper we show that CCR3 is also highly expressed on human blood basophils, as indicated by Northern blotting and flow cytometry, and mediates mainly chemotaxis. Eotaxin and MCP-4 elicited basophil migration in vitro with similar efficacy as regulated upon activation normal T cells expressed and secreted (RANTES) and MCP-3. They also induced the release of histamine and leukotrienes in IL-3-primed basophils, but their efficacy was lower than that of MCP-1 and MCP-3, which were the most potent stimuli of exocytosis. Pretreatment of the basophils with a CCR3-blocking antibody abrogated the migration induced by eotaxin, RANTES, and by low to optimal concentrations of MCP-4, but decreased only minimally the response to MCP-3. The CCR3-blocking antibody also affected exocytosis: it abrogated histamine and leukotriene release induced by eotaxin, and partially inhibited the response to RANTES and MCP-4. In contrast, the antibody did not affect the responses induced by MCP-1, MCP-3, and macrophage inflammatory protein-1alpha, which may depend on CCR1 and CCR2, two additional receptors detected by Northern blotting with basophil RNA. This study demonstrates that CCR3 is the major receptor for eotaxin, RANTES, and MCP-4 in human basophils, and suggests that basophils and eosinophils, which are the characteristic effector cells of allergic inflammation, depend largely on CCR3 for migration towards different chemokines into inflamed tissues.

Full Text

The Full Text of this article is available as a PDF (231.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E., Murphy P. M., Berger E. A. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955–1958. doi: 10.1126/science.272.5270.1955. [DOI] [PubMed] [Google Scholar]
  2. Baggiolini M., Dahinden C. A. CC chemokines in allergic inflammation. Immunol Today. 1994 Mar;15(3):127–133. doi: 10.1016/0167-5699(94)90156-2. [DOI] [PubMed] [Google Scholar]
  3. Baggiolini M., Dewald B., Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705. doi: 10.1146/annurev.immunol.15.1.675. [DOI] [PubMed] [Google Scholar]
  4. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
  5. Baggiolini M. Eotaxin: a VIC (very important chemokine) of allergic inflammation? J Clin Invest. 1996 Feb 1;97(3):587–587. doi: 10.1172/JCI118451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ben-Baruch A., Xu L., Young P. R., Bengali K., Oppenheim J. J., Wang J. M. Monocyte chemotactic protein-3 (MCP3) interacts with multiple leukocyte receptors. C-C CKR1, a receptor for macrophage inflammatory protein-1 alpha/Rantes, is also a functional receptor for MCP3. J Biol Chem. 1995 Sep 22;270(38):22123–22128. doi: 10.1074/jbc.270.38.22123. [DOI] [PubMed] [Google Scholar]
  7. Bischoff S. C., Brunner T., De Weck A. L., Dahinden C. A. Interleukin 5 modifies histamine release and leukotriene generation by human basophils in response to diverse agonists. J Exp Med. 1990 Dec 1;172(6):1577–1582. doi: 10.1084/jem.172.6.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bischoff S. C., Dahinden C. A. Effect of nerve growth factor on the release of inflammatory mediators by mature human basophils. Blood. 1992 May 15;79(10):2662–2669. [PubMed] [Google Scholar]
  9. Bischoff S. C., Krieger M., Brunner T., Dahinden C. A. Monocyte chemotactic protein 1 is a potent activator of human basophils. J Exp Med. 1992 May 1;175(5):1271–1275. doi: 10.1084/jem.175.5.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bischoff S. C., Krieger M., Brunner T., Rot A., von Tscharner V., Baggiolini M., Dahinden C. A. RANTES and related chemokines activate human basophil granulocytes through different G protein-coupled receptors. Eur J Immunol. 1993 Mar;23(3):761–767. doi: 10.1002/eji.1830230329. [DOI] [PubMed] [Google Scholar]
  11. Brunner T., Heusser C. H., Dahinden C. A. Human peripheral blood basophils primed by interleukin 3 (IL-3) produce IL-4 in response to immunoglobulin E receptor stimulation. J Exp Med. 1993 Mar 1;177(3):605–611. doi: 10.1084/jem.177.3.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Charo I. F., Myers S. J., Herman A., Franci C., Connolly A. J., Coughlin S. R. Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2752–2756. doi: 10.1073/pnas.91.7.2752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Choe H., Farzan M., Sun Y., Sullivan N., Rollins B., Ponath P. D., Wu L., Mackay C. R., LaRosa G., Newman W. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun 28;85(7):1135–1148. doi: 10.1016/s0092-8674(00)81313-6. [DOI] [PubMed] [Google Scholar]
  14. Clark-Lewis I., Moser B., Walz A., Baggiolini M., Scott G. J., Aebersold R. Chemical synthesis, purification, and characterization of two inflammatory proteins, neutrophil activating peptide 1 (interleukin-8) and neutrophil activating peptide. Biochemistry. 1991 Mar 26;30(12):3128–3135. doi: 10.1021/bi00226a021. [DOI] [PubMed] [Google Scholar]
  15. Combadiere C., Ahuja S. K., Tiffany H. L., Murphy P. M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol. 1996 Jul;60(1):147–152. doi: 10.1002/jlb.60.1.147. [DOI] [PubMed] [Google Scholar]
  16. Combadiere C., Ahuja S. K., Van Damme J., Tiffany H. L., Gao J. L., Murphy P. M. Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2B. J Biol Chem. 1995 Dec 15;270(50):29671–29675. doi: 10.1074/jbc.270.50.29671. [DOI] [PubMed] [Google Scholar]
  17. Daugherty B. L., Siciliano S. J., DeMartino J. A., Malkowitz L., Sirotina A., Springer M. S. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J Exp Med. 1996 May 1;183(5):2349–2354. doi: 10.1084/jem.183.5.2349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
  19. Gao J. L., Kuhns D. B., Tiffany H. L., McDermott D., Li X., Francke U., Murphy P. M. Structure and functional expression of the human macrophage inflammatory protein 1 alpha/RANTES receptor. J Exp Med. 1993 May 1;177(5):1421–1427. doi: 10.1084/jem.177.5.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Garcia-Zepeda E. A., Combadiere C., Rothenberg M. E., Sarafi M. N., Lavigne F., Hamid Q., Murphy P. M., Luster A. D. Human monocyte chemoattractant protein (MCP)-4 is a novel CC chemokine with activities on monocytes, eosinophils, and basophils induced in allergic and nonallergic inflammation that signals through the CC chemokine receptors (CCR)-2 and -3. J Immunol. 1996 Dec 15;157(12):5613–5626. [PubMed] [Google Scholar]
  21. Gauchat J. F., Henchoz S., Fattah D., Mazzei G., Aubry J. P., Jomotte T., Dash L., Page K., Solari R., Aldebert D. CD40 ligand is functionally expressed on human eosinophils. Eur J Immunol. 1995 Mar;25(3):863–865. doi: 10.1002/eji.1830250335. [DOI] [PubMed] [Google Scholar]
  22. Heath H., Qin S., Rao P., Wu L., LaRosa G., Kassam N., Ponath P. D., Mackay C. R. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J Clin Invest. 1997 Jan 15;99(2):178–184. doi: 10.1172/JCI119145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kitaura M., Nakajima T., Imai T., Harada S., Combadiere C., Tiffany H. L., Murphy P. M., Yoshie O. Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. J Biol Chem. 1996 Mar 29;271(13):7725–7730. doi: 10.1074/jbc.271.13.7725. [DOI] [PubMed] [Google Scholar]
  24. Loetscher P., Seitz M., Baggiolini M., Moser B. Interleukin-2 regulates CC chemokine receptor expression and chemotactic responsiveness in T lymphocytes. J Exp Med. 1996 Aug 1;184(2):569–577. doi: 10.1084/jem.184.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Murphy P. M. Chemokine receptors: structure, function and role in microbial pathogenesis. Cytokine Growth Factor Rev. 1996 Jun;7(1):47–64. doi: 10.1016/1359-6101(96)00009-3. [DOI] [PubMed] [Google Scholar]
  26. Neote K., DiGregorio D., Mak J. Y., Horuk R., Schall T. J. Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor. Cell. 1993 Feb 12;72(3):415–425. doi: 10.1016/0092-8674(93)90118-a. [DOI] [PubMed] [Google Scholar]
  27. Ochensberger B., Daepp G. C., Rihs S., Dahinden C. A. Human blood basophils produce interleukin-13 in response to IgE-receptor-dependent and -independent activation. Blood. 1996 Oct 15;88(8):3028–3037. [PubMed] [Google Scholar]
  28. Ponath P. D., Qin S., Post T. W., Wang J., Wu L., Gerard N. P., Newman W., Gerard C., Mackay C. R. Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils. J Exp Med. 1996 Jun 1;183(6):2437–2448. doi: 10.1084/jem.183.6.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ponath P. D., Qin S., Ringler D. J., Clark-Lewis I., Wang J., Kassam N., Smith H., Shi X., Gonzalo J. A., Newman W. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest. 1996 Feb 1;97(3):604–612. doi: 10.1172/JCI118456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Power C. A., Meyer A., Nemeth K., Bacon K. B., Hoogewerf A. J., Proudfoot A. E., Wells T. N. Molecular cloning and functional expression of a novel CC chemokine receptor cDNA from a human basophilic cell line. J Biol Chem. 1995 Aug 18;270(33):19495–19500. doi: 10.1074/jbc.270.33.19495. [DOI] [PubMed] [Google Scholar]
  31. Qin S., LaRosa G., Campbell J. J., Smith-Heath H., Kassam N., Shi X., Zeng L., Buthcher E. C., Mackay C. R. Expression of monocyte chemoattractant protein-1 and interleukin-8 receptors on subsets of T cells: correlation with transendothelial chemotactic potential. Eur J Immunol. 1996 Mar;26(3):640–647. doi: 10.1002/eji.1830260320. [DOI] [PubMed] [Google Scholar]
  32. Raport C. J., Gosling J., Schweickart V. L., Gray P. W., Charo I. F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. J Biol Chem. 1996 Jul 19;271(29):17161–17166. doi: 10.1074/jbc.271.29.17161. [DOI] [PubMed] [Google Scholar]
  33. Riske F., Hakimi J., Mallamaci M., Griffin M., Pilson B., Tobkes N., Lin P., Danho W., Kochan J., Chizzonite R. High affinity human IgE receptor (Fc epsilon RI). Analysis of functional domains of the alpha-subunit with monoclonal antibodies. J Biol Chem. 1991 Jun 15;266(17):11245–11251. [PubMed] [Google Scholar]
  34. Rot A., Krieger M., Brunner T., Bischoff S. C., Schall T. J., Dahinden C. A. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med. 1992 Dec 1;176(6):1489–1495. doi: 10.1084/jem.176.6.1489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Samson M., Labbe O., Mollereau C., Vassart G., Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362–3367. doi: 10.1021/bi952950g. [DOI] [PubMed] [Google Scholar]
  36. Seder R. A., Paul W. E. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. doi: 10.1146/annurev.iy.12.040194.003223. [DOI] [PubMed] [Google Scholar]
  37. Takafuji S., Bischoff S. C., De Weck A. L., Dahinden C. A. IL-3 and IL-5 prime normal human eosinophils to produce leukotriene C4 in response to soluble agonists. J Immunol. 1991 Dec 1;147(11):3855–3861. [PubMed] [Google Scholar]
  38. Uguccioni M., D'Apuzzo M., Loetscher M., Dewald B., Baggiolini M. Actions of the chemotactic cytokines MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta on human monocytes. Eur J Immunol. 1995 Jan;25(1):64–68. doi: 10.1002/eji.1830250113. [DOI] [PubMed] [Google Scholar]
  39. Uguccioni M., Loetscher P., Forssmann U., Dewald B., Li H., Lima S. H., Li Y., Kreider B., Garotta G., Thelen M. Monocyte chemotactic protein 4 (MCP-4), a novel structural and functional analogue of MCP-3 and eotaxin. J Exp Med. 1996 May 1;183(5):2379–2384. doi: 10.1084/jem.183.5.2379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Van Damme J., Proost P., Lenaerts J. P., Opdenakker G. Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family. J Exp Med. 1992 Jul 1;176(1):59–65. doi: 10.1084/jem.176.1.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weber M., Uguccioni M., Ochensberger B., Baggiolini M., Clark-Lewis I., Dahinden C. A. Monocyte chemotactic protein MCP-2 activates human basophil and eosinophil leukocytes similar to MCP-3. J Immunol. 1995 Apr 15;154(8):4166–4172. [PubMed] [Google Scholar]
  42. Yamagami S., Tanaka H., Endo N. Monocyte chemoattractant protein-2 can exert its effects through the MCP-1 receptor (CC CKR2B). FEBS Lett. 1997 Jan 6;400(3):329–332. doi: 10.1016/s0014-5793(96)01411-1. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES