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Molecular Pharmacology

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Research ArticleArticle

Human Interferon-Inducible 10-kDa Protein and Human Interferon-Inducible T Cell α Chemoattractant Are Allotopic Ligands for Human CXCR3: Differential Binding to Receptor States

Mary Ann Cox, Chung-Her Jenh, Waldemar Gonsiorek, Jay Fine, Satwant K. Narula, Paul J. Zavodny and R. William Hipkin
Molecular Pharmacology April 2001, 59 (4) 707-715; DOI: https://doi.org/10.1124/mol.59.4.707
Mary Ann Cox
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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Chung-Her Jenh
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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Waldemar Gonsiorek
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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Jay Fine
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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Satwant K. Narula
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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Paul J. Zavodny
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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R. William Hipkin
Department of Immunology, Schering-Plough Research Institute, Kenilworth, New Jersey
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Abstract

The human CXC chemokines IP-10 (10-kDa interferon-inducible protein), MIG (monokine induced by human interferon-γ), and I-TAC (interferon-inducible T cell α chemoattractant) attract lymphocytes through activation of CXCR3. In the studies presented here, we examined interaction of these chemokines with human CXCR3 expressed in recombinant cells and human peripheral blood lymphocytes (PBL). IP-10, MIG, and I-TAC were agonists in stimulating [35S]GTPγS binding in recombinant cell and PBL membranes but had no effect in the absence of hCXCR3 expression. 125I-IP-10 and125I-I-TAC bound hCXCR3 with high affinity, although the125I-I-TAC B max value in saturation bindings was 7- to 13-fold higher than that measured with125I-IP-10. Coincubation with unlabeled chemokines decreased 125I-IP-10 binding with a single discernible affinity. However, with 125I-I-TAC, competition with IP-10 or MIG was incomplete, and multiple binding affinities were evident. Moreover, in contrast to I-TAC, IP-10 and MIG binding IC50values did not increase predictably with increased125I-I-TAC concentration in competition bindings, suggesting that these chemokines are noncompetitive (i.e., allotopic) ligands. Uncoupling of hCXCR3 eliminated 125I-IP-10 binding but only decreased 125I-I-TAC binding 30 to 80%, indicating that unlike IP-10, I-TAC binds with high affinity to uncoupled (R) and coupled (R*) hCXCR3. To examine chemokine binding to R*, we tested the effect of anti-hCXCR3 antibody on I-TAC- and IP-10-stimulated [35S]GTPγS binding. The antibody attenuated [35S]GTPγS binding in response to IP-10 but not to I-TAC, suggesting that the two chemokines bind differently toR*. Moreover, increased occupancy of R* with a >75-fold increase in 125I -IP-10 concentration did not increase the I-TAC binding IC50 value, and I-TAC increased the dissociation rate of125I-IP-10. From these data, we conclude that the binding of IP-10 and I-TAC to the R* state of hCXCR3 is allotopic.

Footnotes

    • Received October 6, 2000.
    • Accepted December 7, 2000.
  • Send reprint requests to: R. William Hipkin, Department of Immunology, Schering-Plough Research Institute, Kenilworth, NJ 07033. E-mail: William.Hipkin{at}spcorp.com

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (4)
Molecular Pharmacology
Vol. 59, Issue 4
1 Apr 2001
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Research ArticleArticle

Human Interferon-Inducible 10-kDa Protein and Human Interferon-Inducible T Cell α Chemoattractant Are Allotopic Ligands for Human CXCR3: Differential Binding to Receptor States

Mary Ann Cox, Chung-Her Jenh, Waldemar Gonsiorek, Jay Fine, Satwant K. Narula, Paul J. Zavodny and R. William Hipkin
Molecular Pharmacology April 1, 2001, 59 (4) 707-715; DOI: https://doi.org/10.1124/mol.59.4.707

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Research ArticleArticle

Human Interferon-Inducible 10-kDa Protein and Human Interferon-Inducible T Cell α Chemoattractant Are Allotopic Ligands for Human CXCR3: Differential Binding to Receptor States

Mary Ann Cox, Chung-Her Jenh, Waldemar Gonsiorek, Jay Fine, Satwant K. Narula, Paul J. Zavodny and R. William Hipkin
Molecular Pharmacology April 1, 2001, 59 (4) 707-715; DOI: https://doi.org/10.1124/mol.59.4.707
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