Journal of Leukocyte Biology eBioscience full spectrum cell analysis
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Loetscher, P.
Right arrow Articles by Clark-Lewis, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Loetscher, P.
Right arrow Articles by Clark-Lewis, I.
(Journal of Leukocyte Biology. 2001;69:881-884.)
© 2001 by Society for Leukocyte Biology

Agonistic and antagonistic activities of chemokines

Pius Loetscher* and Ian Clark-Lewis{dagger}

* Theodor Kocher Institute, University of Bern, Bern, Switzerland; and
{dagger} The Biomedical Research Centre and Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada

Correspondence: Pius Loetscher, Theodor Kocher Institute, University of Bern, P.O. Box 99, CH-3000 Bern 9, Switzerland. E-mail: pius.loetscher{at}tki.unibe.ch


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE ROLE OF NH2-TERMINUS...
 THE ROLE OF NH2-TERMINUS...
 NATURAL CHEMOKINES ACTING AS...
 REFERENCES
 
Since the discovery of interleukin-8, about 50 chemokines have been identified and characterized. Originally, they were considered as inducible mediators of inflammation, but in recent years, several chemokines were identified that are expressed constitutively and function in physiological traffic and homing of leukocyte—lymphocytes in particular. All chemokines act via seven-transmembrane domain, G protein-coupled receptors. Eighteen such receptors have been identified so far. Studies on structure-activity relationships indicate that chemokines have two main sites of interaction with their receptors, the flexible NH2-terminal region and the conformationally rigid loop that follows the second cysteine. Chemokines are thought to dock onto receptors by means of the loop region, and this contact is believed to facilitate the binding of the NH2-terminal region that results in receptor activation. These studies have also highlighted the importance of the NH2-terminal region for agonistic and antagonistic activity. Recently, we have shown that some naturally occurring chemokines can function as receptor antagonists. These observations suggest a new mechanism for the regulation of leukocyte recruitment during inflammatory and immune reactions, which are based on the combination of agonistic and antagonistic effects.

Key Words: chemokine receptors • natural antagonists • inflammation • chemotaxis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE ROLE OF NH2-TERMINUS...
 THE ROLE OF NH2-TERMINUS...
 NATURAL CHEMOKINES ACTING AS...
 REFERENCES
 
Chemokines comprise a large family of small, chemoattractant proteins produced by tissue cells and leukocytes, which regulate leukocyte migration in inflammation and immunity [1 2 3 4 5 ]. They consist of 70–130 amino acids and have four conserved cysteines linked to disulfide bonds. Two main subfamilies (CXC and CC chemokines) are distinguished according to the position of the first two cysteines, which are separated by one amino acid (CXC) or are adjacent (CC). Exceptions are lymphotactin (two instead of four cysteines) and fractalkine (three amino acids between the first two cysteines). Based on function and pathophysiological roles, it is possible to distinguish between inflammatory and homing chemokines. Inflammatory chemokines are produced in most tissues under pathological conditions upon stimulation by cytokines and bacterial toxins, and homing chemokines are produced constitutively at homing sites.

All chemokines act via seven-transmembrane domain receptors that are coupled to heterotrimeric guanosine 5'-triphosphate (GTP)-binding proteins [3 , 6 ]. Six receptors for CXC chemokines (CXCRs) and 10 receptors for CC chemokines (CCRs) have been characterized in terms of structure and ligand selectivity. XCR1 is the receptor for lymphotactin and CX3CR1 for fractalkine (Table 1 ). A single chemokine receptor can recognize more than one chemokine, and conversely, a single chemokine can bind more than one receptor. It is interesting to note that the inflammatory chemokines and their receptors are highly promiscuous, and a more selective relationship is observed for the homing chemokines.


View this table:
[in this window]
[in a new window]
  		Table 1. Ligand Selectivity of Human Chemokine Receptors

 
Despite considerable differences in primary sequence, CXC and CC chemokines have a remarkably similar, three-dimensional structure [7 , 8 ]. It is comprised of a short, NH2-terminal region, a large core, which is stabilized by the disulfide bonds and hydrophobic interactions and characterized by three anti-parallel ß-strands, and a COOH-terminal {alpha} helix. The structure of the core is well-ordered, and the NH2-terminal domain and the distal region of the COOH terminus have high-conformational flexibility. Results from many studies of structure-activity relationships suggest that chemokines have two sites of interaction with their receptors, the NH2-terminal region and a discrete domain of the core structure, namely the loop region that follows the second cysteine. The initial interaction (docking) is thought to occur between the loop region and an extracellular domain of the receptor, and this contact is believed to facilitate the access of the NH2-terminal region for receptor activation [7 , 9 10 11 ].

Here, we summarize findings from structure-activity studies, demonstrating the importance of the NH2-terminal region of chemokines for agonistic and antagonistic activity, and present recent evidence that natural chemokines can act as antagonists.


   THE ROLE OF NH2-TERMINUS FOR AGONISTIC ACTIVITY
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF NH2-TERMINUS...
THE ROLE OF NH2-TERMINUS...
 NATURAL CHEMOKINES ACTING AS...
 REFERENCES
 
The first evidence for the importance of the NH2-terminus for activity came from studies with interleukin (IL)-8, which binds with high affinity to CXCR1 and CXCR2 [12 ]. It has been shown by mutagenesis [13 ] and by selective substitution or deletion [14 , 15 ] that the activity of IL-8 depends critically on the Glu-Leu-Arg residues, the so-called ELR motif, immediately preceding the first cysteine. The ELR motif is a characteristic feature of all CXC chemokines that act through CXCR1 and/or CXCR2. It contributes to the high-affinity binding and is the receptor-triggering moiety of the molecule. However, additional, selective binding sites in the ELR chemokines are required. This is suggested by the observation that linear and cyclic ELR-containing peptides are inactive and that neither interferon-inducible protein 10 (IP10) nor monocyte chemoattractant protein-1 (MCP-1) can be converted into IL-8 receptor binding chemokines by introducing the ELR motif at the NH2-terminus [15 ]. Mutation analysis and studies with hybrid chemokines have shown that the loop region (residues 10–17) and the Gly31-Pro32 motif before the third cysteine are of primary importance [7 , 16 ]. The secondary binding site determines the affinity for binding to CXCR1 and CXCR2 [8 ].

More recent studies have shown that the NH2-terminal region of SDF-1 is also essential for receptor binding and activation [9 , 17 ]. Like IL-8, SDF-1 is a CXC chemokine, but it lacks the ELR motif. It is the unique ligand for CXCR4 that is expressed widely on leukocytes and tissue cells [6 ]. Structure-activity relations were studied with a broad panel of analogs obtained by truncation, amino-acid substitution, and the synthesis of chimeric chemokines [9 ]. The results show that the eight NH2-terminal residues are important for receptor binding and that only the first two (Lys1-Pro2) are involved in receptor activation. Deletion of Lys1, yielding SDF-1(2–67), results in a dramatic decrease in the activity on T lymphocytes, and deletion of Pro2 as well as of the next six residues [SDF-1(3–67) through SDF-1(9–67)] leads to a complete loss of activity. Despite the inability to induce receptor activation, SDF-1(2–67) and SDF-1(3–67) retain a marked binding affinity for CXCR4 and thus act as antagonists (see below). Of particular interest is the observation that oligopeptides corresponding to the NH2-terminal sequence of SDF-1 [SDF-1(1–8) and SDF-1(1–9)] are active biologically, although much less potent than the parent chemokine [17 ]. SDF-1(1–8) and SDF-1(1–9) bind to CXCR4 and induce [Ca2+]i changes and chemotaxis in T lymphocytes and a human lymphoblastoid CD4+ T cell line (CEM) cells. In addition, substitution of the NH2-terminus of IP10 or growth-related oncogene {alpha} (GRO{alpha}) with that of SDF-1 results in chimeras with SDF-1 activity [9 ]. As for IL-8, some residues in the loop region of SDF-1, the so-called REFESH motif (residues 12–17), contribute to the binding and are proposed to act as the docking site of SDF-1 on CXCR4 [9 ]. In fact, the NH2-terminal peptide, SDF-1(1–17), which includes the RFFESH motif, has a higher affinity for CXCR4 and is more potent than SDF-1(1–8) or SDF-1(1–9) [17 ]. This peptide has been shown recently to adopt a defined structure in solution, which may mimic the receptor-bound conformation [18 ]. The residues within the REFESH region that are important for function have not been determined.

Studies with truncated derivatives of the CC chemokines including MCP-1, MCP-3, and RANTES (regulated on activation, normal T expressed and secreted) have provided further evidence for the role of the sequence preceding the first cysteine for receptor recognition and activation [7 , 8 ]. However, as shown for MCP-1, the structural requirements are stricter, because the intact NH2-terminal sequence appears to be necessary. Considerable loss of activity is observed after NH2-terminal truncation or elongation, but replacement of NH2-terminal pyroglutamate by several noncyclic residues is tolerated [19 ].


   THE ROLE OF NH2-TERMINUS FOR ANTAGONISTIC ACTIVITY
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF NH2-TERMINUS...
 THE ROLE OF NH2-TERMINUS...
NATURAL CHEMOKINES ACTING AS...
 REFERENCES
 
Not only the agonistic, but also the antagonistic activity of chemokines is critically dependent on the NH2-terminal region [20 ]. Modifications of the NH2-terminus can lead to derivatives that still recognize the receptor but do not signal and thus act as antagonists. The first such antagonist was obtained by NH2-terminal truncation of IL-8 [21 ]. (R)IL-8, an analog obtained by deletion of the first five NH2-terminal residues, is inactive on neutrophils but inhibits the binding of IL-8 and other ELR chemokines to CXCR1 and CXCR2. Substitutions within the ELR motif also yield antagonists, with (AAR)IL-8 being the most potent derivative [21 ]. Antagonists are also generated by truncation of other ELR chemokines, including GRO{alpha}, and of the ELR-PF4 analog, which has high affinity for CXCR2 but only low affinity for CXCR1. Binding competition and inhibition of functional responses show that (R)GRO{alpha} and (R)PF4 block CXCR2 selectively, whereas (R)IL-8 and (AAR)IL-8 block CXCR1 and CXCR2 [22 ]. Several antagonists are obtained by modification of the first two NH2-terminal residues of SDF-1. SDF-1(P2G), an analog in which Pro2 is substituted with Gly, is the most potent CXCR4 antagonist [9 ].

NH2 terminally truncated CC chemokines can also act as antagonists. MCP-1, MCP-3, and RANTES are examples that are extensively studied [8 ]. For instance, MCP-1 lacking the first eight NH2-terminal residues, MCP-1(9–76), blocks CCR2 and prevents responses induced by MCP-1, MCP-2, and MCP-3 but not by RANTES, MIP-1{alpha}, and MIP-1ß [19 ]. In contrast, the truncation derivatives RANTES(9–68), MCP-3(5–76), and MCP-3(10–76) block CCR1, CCR2, CCR3, and CCR5 and inhibit responses elicited by MCP-1, MCP-3, RANTES, and MIP-1{alpha} [23 , 24 ]. In addition, antagonists are obtained by NH2-terminal elongation of MCP-3 with Arg-Glu-Phe [25 ] or RANTES with a methionine [26 ]. Another modification of RANTES, NH2-terminal elongation with aminooxypentane (AOP), was demonstrated originally to yield an antagonist [27 ]. Subsequently, it was shown, however, that AOP-RANTES is actually an agonist for CCR3, CCR5, and to a lesser extent, CCR1 [28 29 30 31 ]. A recent study has shown that dendritic cell chemokine1 (DC-CK1) can be converted into a potent and specific antagonist for CCR3 by substituting the NH2-terminal alanine with a methionine [32 ]. It should be noted that the receptor for DC-CK1, which was shown to attract T lymphocytes, is unknown still [33 , 34 ].

It is important to keep in mind that NH2-terminal truncation does not yield CXC or CC chemokine antagonists necessarily. For instance, IP10 and eotaxin lose the capacity to bind to CXCR3 and CCR3, respectively, when only a few NH2-terminal residues are deleted (unpublished results).


   NATURAL CHEMOKINES ACTING AS ANTAGONISTS
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF NH2-TERMINUS...
 THE ROLE OF NH2-TERMINUS...
 NATURAL CHEMOKINES ACTING AS...
REFERENCES
 
While studying the activities of several chemokines on Th1 and Th2 lymphocytes, we found recently that the agonists for CXCR3 act as antagonists for CCR3 [35 ]. I-TAC, Mig, and IP10 are the selective attractants for CXCR3-expressing Th1 cells, whereas eotaxin and several other CC chemokines bind to CCR3, which is expressed on Th2 cells, eosinophils, and basophils [36 37 38 39 40 41 ]. Conversely, unmodified I-TAC, Mig, and IP10 compete for the binding of eotaxin to CCR3 and inhibit migration and Ca2+ changes in CCR3-expressing cells in response to eotaxin, eotaxin-2, MCP-2, MCP-3, MCP-4, and RANTES. Binding competition and inhibition of the functional responses show that I-TAC is the most potent antagonist followed by Mig and IP10. It is interesting that the same potency ranking is observed for the agonistic activity mediated via CXCR3, suggesting the existence of binding-relevant homologies between CXCR3 and CCR3. The antagonistic effect of I-TAC is restricted largely to CCR3. Of all other chemokine receptors tested, only CCR5 is blocked slightly by I-TAC. In the attempt to enhance the antagonistic effect, we have generated a hybrid chemokine by substituting the first eight NH2-terminal residues of eotaxin with those of I-TAC. The resulting hybrid, I-TAC/EoH1, binds CCR3 with higher affinity than eotaxin and I-TAC (threefold and tenfold, respectively) and is about fivefold more potent than I-TAC as an inhibitor of the effects of eotaxin. I-TAC, Mig, IP10, and I-TAC/EoH1 do not induce CCR3 internalization, indicating, together with the functional data, that they lack agonistic activity and thus qualify as pure CCR3 antagonists.

These findings suggest a new mechanism for the regulation of leukocyte recruitment during inflammatory and immune reactions by chemokines, which is based on the combination of agonistic and antagonistic effects (Fig. 1 ). It is interesting to note that I-TAC, Mig, and IP10, which attract CXCR3-bearing cells, are induced by interferon-{gamma} (IFN-{gamma}) [42 , 43 ], whereas eotaxin, a specific agonist for CCR3, is induced by IL-4 [44 ]. The infiltrate observed in the presence of IFN-{gamma} is rich in Th1 cells, and Th2 cells predominate under the influence of IL-4. Therefore, CXCR3-selective chemokines may enhance this polarization by acting as antagonists of CCR3 and thus inhibiting the infiltration of Th2 cells, in addition to their effect as attractants of Th1 cells via CXCR3.



View larger version (32K):
[in this window]
[in a new window]
  		Figure 1. Model for the regulation of leukocyte recruitment by chemokines based on a combination of agonistic and antagonistic activity. Th1 cells express CXCR3, which binds I-TAC, Mig, and IP10, whereas Th2 cells, eosinophils, and basophils express CCR3, which binds the eotaxins, MCP-2 to 4, MEC, and RANTES. I-TAC, Mig, and IP10, which are induced by IFN-{gamma}, attract CXCR3-bearing cells by acting as agonists and inhibit the recruitment of CCR3-bearing cells concomitantly by acting as antagonists. CCR3 agonists, in particular eotaxin-1, are induced by IL-4.

 
Two other recent studies present evidence that antagonistic activity of natural chemokines is not restricted to I-TAC, Mig, and IP10. Eotaxin is shown to be a natural antagonist for CCR2 [45 ] and MCP-3 for CCR5 [46 ]. Eotaxin competes for the binding of MCP-1 to CCR2 on monocytes and inhibits MCP-1-induced chemotaxis and enzyme release. Similarly, MCP-3 binds to CCR5 without signaling and has the capacity to block CCR5-mediated functional responses. Eotaxin and MCP-3 do not induce internalization of CCR2 and CCR5, respectively. These activities could reflect an in vivo role for the fine-tuning of cellular responses occurring at sites of inflammation.


   ACKNOWLEDGEMENTS
 
This work was supported by grant 31-55996.98 from the Swiss National Science Foundation and by the Protein Engineering Network Centres of Excellence (Canada) and the Arthritis Society (Canada). We thank M. Baggiolini for critical reading of the manuscript.

Received January 9, 2001; revised February 21, 2001; accepted February 22, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF NH2-TERMINUS...
 THE ROLE OF NH2-TERMINUS...
 NATURAL CHEMOKINES ACTING AS...
 REFERENCES
 

  1. Baggiolini, M. (1998) Chemokines and leukocyte traffic Nature 392,565-568[Medline]
  2. Sallusto, F., Mackay, C. R., Lanzavecchia, A. (2000) The role of chemokine receptors in primary, effector, and memory immune responses Annu. Rev. Immunol. 18,593-620[Medline]
  3. Loetscher, P., Moser, B., Baggiolini, M. (2000) Chemokines and their receptors in lymphocyte traffic and HIV infection Adv. Immunol. 74,127-180[Medline]
  4. Cyster, J. G. (1999) Chemokines and cell migration in secondary lymphoid organs Science 286,2098-2102[Abstract/Free Full Text]
  5. Zlotnik, A., Yoshie, O. (2000) Chemokines: a new classification system and their role in immunity Immunity 12,121-127[Medline]
  6. Murphy, P. M., Baggiolini, M., Charo, I. F., Hebert, C. A., Horuk, R., Matsushima, K., Miller, L. H., Oppenheim, J. J., Power, C. A. (2000) International union of pharmacology. XXII. Nomenclature for chemokine receptors Pharmacol. Rev. 52,145-176[Abstract/Free Full Text]
  7. Clark-Lewis, I., Kim, K-S., Rajarathnam, K., Gong, J-H., Dewald, B., Moser, B., Baggiolini, M., Sykes, B. D. (1995) Structure-activity relationships of chemokines J. Leukoc. Biol. 57,703-711[Abstract]
  8. Baggiolini, M., Dewald, B., Moser, B. (1997) Human chemokines: an update Annu. Rev. Immunol. 15,675-705[Medline]
  9. Crump, M. P., Gong, J. H., Loetscher, P., Rajarathnam, K., Amara, A., Arenzana-Seisdedos, F., Virelizier, J. L., Baggiolini, M., Sykes, B. D., Clark-Lewis, I. (1997) Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1 EMBO J 16,6996-7007[Medline]
  10. Crump, M. P., Rajarathnam, K., Kim, K. S., Clark-Lewis, I., Sykes, B. D. (1998) Solution structure of eotaxin, a chemokine that selectively recruits eosinophils in allergic inflammation J. Biol. Chem. 273,22471-22479[Abstract/Free Full Text]
  11. Monteclaro, F. S., Charo, I. F. (1996) The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1 {alpha} receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation J. Biol. Chem. 271,19084-19092[Abstract/Free Full Text]
  12. Baggiolini, M., Dewald, B., Moser, B. (1994) Interleukin-8 and related chemotactic cytokines—CXC and CC chemokines Adv. Immunol. 55,97-179[Medline]
  13. Hébert, C. A., Vitangcol, R. V., Baker, J. B. (1991) Scanning mutagenesis of interleukin-8 identifies a cluster of residues required for receptor binding J. Biol. Chem. 266,18989-18994[Abstract/Free Full Text]
  14. Clark-Lewis, I., Schumacher, C., Baggiolini, M., Moser, B. (1991) Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemotaxis, exocytosis, and receptor binding activities J. Biol. Chem. 266,23128-23134[Abstract/Free Full Text]
  15. Clark-Lewis, I., Dewald, B., Geiser, T., Moser, B., Baggiolini, M. (1993) Platelet factor 4 binds to interleukin 8 receptors and activates neutrophils when its N terminus is modified with Glu-Leu-Arg Proc. Natl. Acad. Sci. USA 90,3574-3577[Abstract/Free Full Text]
  16. Clark-Lewis, I., Dewald, B., Loetscher, M., Moser, B., Baggiolini, M. (1994) Structural requirements for interleukin-8 function identified by design of analogs and CXC chemokine hybrids J. Biol. Chem. 269,16075-16081[Abstract/Free Full Text]
  17. Loetscher, P., Gong, J. H., Dewald, B., Baggiolini, M., Clark-Lewis, I. (1998) N-terminal peptides of stromal cell-derived factor-1 with CXC chemokine receptor 4 agonist and antagonist activities J. Biol. Chem. 273,22279-22283[Abstract/Free Full Text]
  18. Elisseeva, E. L., Slupsky, C. M., Crump, M. P., Clark-Lewis, I., Sykes, B. D. (2000) NMR studies of active N-terminal peptides of stromal cell-derived factor-1. Structural basis for receptor binding J. Biol. Chem. 275,26799-26805[Abstract/Free Full Text]
  19. Gong, J-H., Clark-Lewis, I. (1995) Antagonists of monocyte chemoattractant protein 1 identified by modification of functionally critical NH2-terminal residues J. Exp. Med. 181,631-640[Abstract/Free Full Text]
  20. Baggiolini, M., Moser, B. (1997) Blocking chemokine receptors J. Exp. Med. 186,1189-1191[Free Full Text]
  21. Moser, B., Dewald, B., Barella, L., Schumacher, C., Baggiolini, M., Clark-Lewis, I. (1993) Interleukin-8 antagonists generated by N-terminal modification J. Biol. Chem. 268,7125-7128[Abstract/Free Full Text]
  22. Jones, S. A., Dewald, B., Clark-Lewis, I., Baggiolini, M. (1997) Chemokine antagonists that discriminate between interleukin-8 receptors. Selective blockers of CXCR2 J. Biol. Chem. 272,16166-16169[Abstract/Free Full Text]
  23. Gong, J-H., Uguccioni, M., Dewald, B., Baggiolini, M., Clark-Lewis, I. (1996) RANTES and MCP-3 antagonists bind multiple chemokine receptors J. Biol. Chem. 271,10521-10527[Abstract/Free Full Text]
  24. McQuibban, G. A., Gong, J. H., Tam, E. M., McCulloch, C. A., Clark-Lewis, I., Overall, C. M. (2000) Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3 Science 289,1202-1206[Abstract/Free Full Text]
  25. Masure, S., Paemen, L., Proost, P., Van Damme, J., Opdenakker, G. (1995) Expression of a human mutant monocyte chemotactic protein 3 in Pichia pastoris and characterization as an MCP-3 receptor antagonist J. Interferon Cytokine Res. 15,955-963[Medline]
  26. Proudfoot, A. E., Power, C. A., Hoogewerf, A. J., Montjovent, M. O., Borlat, F., Offord, R. E., Wells, T. N. (1996) Extension of recombinant human RANTES by the retention of the initiating methionine produces a potent antagonist J. Biol. Chem. 271,2599-2603[Abstract/Free Full Text]
  27. Simmons, G., Clapham, P. R., Picard, L., Offord, R. E., Rosenkilde, M. M., Schwartz, T. W., Buser, R., Wells, T. N. C., Proudfoot, A. E. I. (1997) Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist Science 276,276-279[Abstract/Free Full Text]
  28. Mack, M., Luckow, B., Nelson, P. J., Cihak, J., Simmons, G., Clapham, P. R., Signoret, N., Marsh, M., Stangassinger, M., Borlat, F., Wells, T. N., Schlondorff, D., Proudfoot, A. E. (1998) Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity J. Exp. Med. 187,1215-1224[Abstract/Free Full Text]
  29. Rodríguez-Frade, J. M., Vila-Coro, A. J., Martín, A., Nieto, M., Sánchez-Madrid, F., Proudfoot, A. E. I., Wells, T. N. C., Martínez, C., Mellado, M. (1999) Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis J. Cell Biol. 144,755-765[Abstract/Free Full Text]
  30. Proudfoot, A. E. I., Buser, R., Borlat, F., Alouani, S., Soler, D., Offord, R. E., Schröder, J. M., Power, C. A., Wells, T. N. C. (1999) Amino-terminally modified RANTES analogues demonstrate differential effects on RANTES receptors J. Biol. Chem. 274,32478-32485[Abstract/Free Full Text]
  31. Elsner, J., Mack, M., Bruhl, H., Dulkys, Y., Kimmig, D., Simmons, G., Clapham, P. R., Schlondorff, D., Kapp, A., Wells, T. N., Proudfoot, A. E. (2000) Differential activation of CC chemokine receptors by AOP-RANTES J. Biol. Chem. 275,7787-7794[Abstract/Free Full Text]
  32. Nibbs, R. J., Salcedo, T. W., Campbell, J. D., Yao, X. T., Li, Y., Nardelli, B., Olsen, H. S., Morris, T. S., Proudfoot, A. E., Patel, V. P., Graham, G. J. (2000) C-C chemokine receptor 3 antagonism by the beta-chemokine macrophage inflammatory protein 4, a property strongly enhanced by an amino-terminal alanine-methionine swap J. Immunol. 164,1488-1497[Abstract/Free Full Text]
  33. Adema, G. J., Hartgers, F., Verstraten, R., De Vries, E., Marland, G., Menon, S., Foster, J., Xu, Y. M., Nooyen, P., McClanahan, T., Bacon, K. B., Figdor, C. G. (1997) A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells Nature 387,713-717[Medline]
  34. Hieshima, K., Imai, T., Baba, M., Shoudai, K., Ishizuka, K., Nakagawa, T., Tsuruta, J., Takeya, M., Sakaki, Y., Takatsuki, K., Miura, R., Opdenakker, G., Van Damme, J., Yoshie, O., Nomiyama, H. (1997) A novel human CC chemokine PARC that is most homologous to macrophage-inflammatory protein-1{alpha}/LD78{alpha} and chemotactic for T lymphocytes, but not for monocytes J. Immunol. 159,1140-1149[Abstract]
  35. Loetscher, P., Pellegrino, A., Gong, J. H., Mattioli, I., Loetscher, M., Bardi, G., Baggiolini, M., Clark-Lewis, I. (2001) The ligands of CXC chemokine receptor 3, I-TAC, Mig, and IP10, are natural antagonists for CCR3 J. Biol. Chem. 276,2986-2991[Abstract/Free Full Text]
  36. Bonecchi, R., Bianchi, G., Bordignon, P. P., D’Ambrosio, D., Lang, R., Borsatti, A., Sozzani, S., Allavena, P., Gray, P. A., Mantovani, A., Sinigaglia, F. (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s J. Exp. Med. 187,129-134[Abstract/Free Full Text]
  37. Sallusto, F., Lenig, D., Mackay, C. R., Lanzavecchia, A. (1998) Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes J. Exp. Med. 187,875-883[Abstract/Free Full Text]
  38. Sallusto, F., Mackay, C. R., Lanzavecchia, A. (1997) Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells Science 277,2005-2007[Abstract/Free Full Text]
  39. Loetscher, P., Uguccioni, M., Bordoli, L., Baggiolini, M., Moser, B., Chizzolini, C., Dayer, J. M. (1998) CCR5 is characteristic of Th1 lymphocytes Nature 391,344-345[Medline]
  40. Gerber, B. O., Zanni, M. P., Uguccioni, M., Loetscher, M., Mackay, C. R., Pichler, W. J., Yawalkar, N., Baggiolini, M., Moser, B. (1997) Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils Curr. Biol. 7,836-843[Medline]
  41. Uguccioni, M., Mackay, C. R., Ochensberger, B., Loetscher, P., Rhis, S., LaRosa, G. J., Rao, P., Ponath, P. D., Baggiolini, M., Dahinden, C. A. (1997) High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines J. Clin. Invest. 100,1137-1143[Medline]
  42. Cole, K. E., Strick, C. A., Paradis, T. J., Ogborne, K. T., Loetscher, M., Gladue, R. P., Lin, W., Boyd, J. G., Moser, B., Wood, D. E., Sahagan, B. G., Neote, K. (1998) Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3 J. Exp. Med. 187,2009-2021[Abstract/Free Full Text]
  43. Sauty, A., Dziejman, M., Taha, R. A., Iarossi, A. S., Neote, K., Garcia-Zepeda, E. A., Hamid, Q., Luster, A. D. (1999) The T cell-specific CXC chemokines IP-10, Mig, and I-TAC are expressed by activated human bronchial epithelial cells J. Immunol. 162,3549-3558[Abstract/Free Full Text]
  44. Mochizuki, M., Bartels, J., Mallet, A. I., Christophers, E., Schröder, J. M. (1998) IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in helminth infection and atopy J. Immunol. 160,60-68[Abstract/Free Full Text]
  45. Ogilvie, P., Bardi, G., Clark-Lewis, I., Baggiolini, M., Uguccioni, M. (2001) Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5 Blood 97,1920-1924[Abstract/Free Full Text]
  46. Blanpain, C., Migeotte, I., Lee, B., Vakili, J., Doranz, B. J., Govaerts, C., Vassart, G., Doms, R. W., Parmentier, M. (1999) CCR5 binds multiple CC-chemokines: MCP-3 acts as a natural antagonist Blood 94,1899-1905[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cancer Res.Home page
N. Giuliani, G. Lisignoli, S. Colla, M. Lazzaretti, P. Storti, C. Mancini, S. Bonomini, C. Manferdini, K. Codeluppi, A. Facchini, et al.
CC-Chemokine Ligand 20/Macrophage Inflammatory Protein-3{alpha} and CC-Chemokine Receptor 6 Are Overexpressed in Myeloma Microenvironment Related to Osteolytic Bone Lesions
Cancer Res., August 15, 2008; 68(16): 6840 - 6850.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
P. Van Lint and C. Libert
Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation
J. Leukoc. Biol., December 1, 2007; 82(6): 1375 - 1381.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Cittera, M. Leidi, C. Buracchi, F. Pasqualini, S. Sozzani, A. Vecchi, J. D. Waterfield, M. Introna, and J. Golay
The CCL3 Family of Chemokines and Innate Immunity Cooperate In Vivo in the Eradication of an Established Lymphoma Xenograft by Rituximab
J. Immunol., May 15, 2007; 178(10): 6616 - 6623.
[Abstract] [Full Text] [PDF]

Home page
 Rheumatology (Oxford)Home page
T. Garrood, L. Lee, and C. Pitzalis
Molecular mechanisms of cell recruitment to inflammatory sites: general and tissue-specific pathways
Rheumatology, March 1, 2006; 45(3): 250 - 260.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
K. Balabanian, B. Lagane, S. Infantino, K. Y. C. Chow, J. Harriague, B. Moepps, F. Arenzana-Seisdedos, M. Thelen, and F. Bachelerie
The Chemokine SDF-1/CXCL12 Binds to and Signals through the Orphan Receptor RDC1 in T Lymphocytes
J. Biol. Chem., October 21, 2005; 280(42): 35760 - 35766.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. Casarosa, M. Waldhoer, P. J. LiWang, H. F. Vischer, T. Kledal, H. Timmerman, T. W. Schwartz, M. J. Smit, and R. Leurs
CC and CX3C Chemokines Differentially Interact with the N Terminus of the Human Cytomegalovirus-encoded US28 Receptor
J. Biol. Chem., February 4, 2005; 280(5): 3275 - 3285.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
R. L. Jones, N. J. Hannan, T. J. Kaitu'u, J. Zhang, and L. A. Salamonsen
Identification of Chemokines Important for Leukocyte Recruitment to the Human Endometrium at the Times of Embryo Implantation and Menstruation
J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6155 - 6167.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
B Moser and K Willimann
Chemokines: role in inflammation and immune surveillance
Ann Rheum Dis, November 1, 2004; 63(suppl_2): ii84 - ii89.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
T. Dajotoy, P. Andersson, A. Bjartell, C.-G. Lofdahl, H. Tapper, and A. Egesten
Human eosinophils produce the T cell-attracting chemokines MIG and IP-10 upon stimulation with IFN-{gamma}
J. Leukoc. Biol., September 1, 2004; 76(3): 685 - 691.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
U. Forssmann, I. Hartung, R. Balder, B. Fuchs, S. E. Escher, N. Spodsberg, Y. Dulkys, M. Walden, A. Heitland, A. Braun, et al.
n-Nonanoyl-CC Chemokine Ligand 14, a Potent CC Chemokine Ligand 14 Analogue That Prevents the Recruitment of Eosinophils in Allergic Airway Inflammation
J. Immunol., September 1, 2004; 173(5): 3456 - 3466.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
H. Fernando, C. Chin, J. Rosgen, and K. Rajarathnam
Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor
J. Biol. Chem., August 27, 2004; 279(35): 36175 - 36178.
[Abstract] [Full Text] [PDF]

Home page
 Protein Sci.Home page
V. Booth, I. Clark-Lewis, and B. D. Sykes
NMR structure of CXCR3 binding chemokine CXCL11 (ITAC)
Protein Sci., August 1, 2004; 13(8): 2022 - 2028.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. Rajagopalan and K. Rajarathnam
Ligand Selectivity and Affinity of Chemokine Receptor CXCR1: ROLE OF N-TERMINAL DOMAIN
J. Biol. Chem., July 16, 2004; 279(29): 30000 - 30008.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
P. Ogilvie, S. Thelen, B. Moepps, P. Gierschik, A. C. da Silva Campos, M. Baggiolini, and M. Thelen
Unusual Chemokine Receptor Antagonism Involving a Mitogen-Activated Protein Kinase Pathway
J. Immunol., June 1, 2004; 172(11): 6715 - 6722.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
V. Petkovic, C. Moghini, S. Paoletti, M. Uguccioni, and B. Gerber
Eotaxin-3/CCL26 Is a Natural Antagonist for CC Chemokine Receptors 1 and 5: A HUMAN CHEMOKINE WITH A REGULATORY ROLE
J. Biol. Chem., May 28, 2004; 279(22): 23357 - 23363.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. Vroon, C. J. Heijnen, R. Raatgever, I. P. Touw, R. E. Ploemacher, R. T. Premont, and A. Kavelaars
GRK6 deficiency is associated with enhanced CXCR4-mediated neutrophil chemotaxis in vitro and impaired responsiveness to G-CSF in vivo
J. Leukoc. Biol., April 1, 2004; 75(4): 698 - 704.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
F. C. Peterson, E. S. Elgin, T. J. Nelson, F. Zhang, T. J. Hoeger, R. J. Linhardt, and B. F. Volkman
Identification and Characterization of a Glycosaminoglycan Recognition Element of the C Chemokine Lymphotactin
J. Biol. Chem., March 26, 2004; 279(13): 12598 - 12604.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
R. V. Warke, K. Xhaja, K. J. Martin, M. F. Fournier, S. K. Shaw, N. Brizuela, N. de Bosch, D. Lapointe, F. A. Ennis, A. L. Rothman, et al.
Dengue Virus Induces Novel Changes in Gene Expression of Human Umbilical Vein Endothelial Cells
J. Virol., November 1, 2003; 77(21): 11822 - 11832.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
P. Ogilvie, S. Paoletti, I. Clark-Lewis, and M. Uguccioni
Eotaxin-3 is a natural antagonist for CCR2 and exerts a repulsive effect on human monocytes
Blood, August 1, 2003; 102(3): 789 - 794.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Vulcano, S. Struyf, P. Scapini, M. Cassatella, S. Bernasconi, R. Bonecchi, A. Calleri, G. Penna, L. Adorini, W. Luini, et al.
Unique Regulation of CCL18 Production by Maturing Dendritic Cells
J. Immunol., April 1, 2003; 170(7): 3843 - 3849.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
I. Clark-Lewis, I. Mattioli, J.-H. Gong, and P. Loetscher
Structure-Function Relationship between the Human Chemokine Receptor CXCR3 and Its Ligands
J. Biol. Chem., January 3, 2003; 278(1): 289 - 295.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
M. E. Rosenfeld
Leukocyte Recruitment Into Developing Atherosclerotic Lesions: The Complex Interaction Between Multiple Molecules Keeps Getting More Complex
Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 361 - 363.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Loetscher, P.
Right arrow Articles by Clark-Lewis, I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Loetscher, P.
Right arrow Articles by Clark-Lewis, I.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS