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Differential Activation and Regulation of CXCR1 and CXCR2 by CXCL8 Monomer and Dimer¹

Mohd W. Nasser^*, Sandeep K. Raghuwanshi^*, Delores J. Grant^*, Venkatakrishna R. Jala, Krishna Rajarathnam^2, and Ricardo M. Richardson^2,*

^* Julius L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology, North Carolina Central University, Durham, NC 27707; James Graham Brown Cancer Center and Department of Microbiology & Immunology, University of Louisville Health Sciences Center, Louisville, Kentucky 40202; and Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555

CXCL8 (also known as IL-8) activates CXCR1 and CXCR2 to mediate neutrophil recruitment and trigger cytotoxic effect at sites of infection. Under physiological conditions, CXCL8 could exist as monomers, dimers, or a mixture of monomers and dimers. Therefore, both forms of CXCL8 could interact with CXCR1 and CXCR2 with different affinities and potencies to mediate different cellular responses. In the present study, we have used a "trapped" nonassociating monomer (L25NMe) and a nondissociating dimer (R26C) to investigate their activities for human neutrophils that express both receptors and for RBL-2H3 cells stably expressing either CXCR1(RBL-CXCR1) or CXCR2 (RBL-CXCR2). The monomer was more active than the dimer for activities such as intracellular Ca²⁺ mobilization, phosphoinositide hydrolysis, chemotaxis. and exocytosis. Receptor regulation, however, is distinct for each receptor. The rate of monomer-mediated regulation of CXCR1 is greater for activities such as phosphorylation, desensitization, β-arrestin translocation, and internalization. In contrast, for CXCR2, both monomeric and dimeric CXCL8 mediate these activities to a similar extent. Interestingly, receptor-mediated signal-regulated kinase (ERK) phosphorylation in response to all three CXCL8 variants was more sustained for CXCR2 relative to CXCR1. Taken together, the results indicate that the CXCL8 monomer and dimer differentially activate and regulate CXCR1 and CXCR2 receptors. These distinct properties of the ligand and the receptors play a critical role in orchestrating neutrophil recruitment and eliciting cytotoxic activity during an inflammatory response.

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.

¹ This work was supported by National Institutes of Health Grants AI38910 and 056-CA92077 (to R.M.R.) and AI069152 (to K.R.) and by the U.S. Army Medical Research and Materiel Command (07-1-0418 (to R.M.R.).

² Address correspondence and reprint requests to Dr. Ricardo M. Richardson, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 1801 Fayetteville Street, Durham, NC 27707. E-mail address: mrrichardson{at}nccu.edu or Dr. Krishna Rajarathnam, Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555. E-mail address: krratara{at}utmb.edu

³ Abbreviations used in this paper: IP, inositol phosphate; βarr, β-arrestin; GPCR, G-protein-coupled receptor; WT, wild type; HMEC, human microvascular endothelial cell.