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J. Biol. Chem., Vol. 279, Issue 35, 36175-36178, August 27, 2004

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Dimer Dissociation Is Essential for Interleukin-8 (IL-8) Binding to CXCR1 Receptor^*

Harshica Fernando, Christopher Chin, Jörg Rösgen, and Krishna Rajarathnam

From the Department of Human Biological Chemistry and Genetics and Sealy Center for Structural Biology, University of Texas Medical Branch, Galveston, Texas 77555-1055

Chemokines play a fundamental role in trafficking of immune cells and in host defense against infection. The role of chemokines in the recruitment process is highly regulated spatially and temporally and involves interactions with G protein-coupled receptors and cell surface glycosaminoglycans. The dynamic equilibrium between chemokine monomers and dimers, both free in solution and in cell surface-bound forms, regulates different components of recruitment such as chemotaxis and receptor signaling. The binding and activity of the chemokine interleukin-8 (IL-8) for its receptors, previously studied using "trapped" non-associating monomers and non-dissociating dimers, show that the monomer has a native-like function but support conflicting roles for the dimer. We have measured the binding of native IL-8 to the CXCR1 N-domain, using isothermal titration calorimetry and sedimentation equilibrium techniques. The N-domain constitutes a critical binding site, and IL-8 binding affinity to the receptor N-domain is in the same concentration range as the IL-8 monomerdimer equilibrium. We observed that only the IL-8 monomer, and not the dimer, is competent in binding the receptor N-domain. Based on our results, we propose that IL-8 dimerization functions as a negative regulator for the receptor function and as a positive regulator for binding to glycosaminoglycans and that both play a role in the neutrophil recruitment process.

Received for publication, June 17, 2004 , and in revised form, July 8, 2004.

^* This work was supported by American Heart Association Texas Affiliate Grant 0365112Y (to K. R.) and by a training fellowship from the W. M. Keck Foundation (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We dedicate this work in memory of Dr. Ian Clark-Lewis.

To whom correspondence should be addressed. Tel.: 409-772-2238; Fax: 409-772-1790; E-mail: krrajara{at}utmb.edu.

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