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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 464-472, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0084OC

Binding of Interleukin-8 to Heparan Sulfate and Chondroitin Sulfate in Lung Tissue

Charles W. Frevert, Michael G. Kinsella, Charie Vathanaprida, Richard B. Goodman, Denis G. Baskin, Amanda Proudfoot, Timothy N. C. Wells, Thomas N. Wight and Thomas R. Martin

Medical Research Service, VA Puget Sound Medical Center, Seattle; Division of Pulmonary and Critical and Care Medicine, Division of Metabolism Endocrinology and Nutrition, and Department of Medicine, University of Washington School of Medicine, Seattle; Department of Vascular Biology, Hope Heart Institute, Seattle, Washington; and Serono Pharmaceutical Research Institute, Geneva, Switzerland

Address correspondence to: Charles W. Frevert, D.V.M., Sc.D., Seattle VAMC Pulmonary Research Group, Seattle VA Medical Center, 151L, 1660 S. Columbian Way, Seattle, WA 98108. E-mail: cfrevert{at}u.washington.edu

Interleukin (IL)-8, a member of the CXC chemokine family, is a potent neutrophil chemotactic factor. Mechanisms that regulate the activity of chemokines in tissue are not clear. The goal of this study was to determine whether IL-8–glycosaminoglycan interactions are responsible for the binding of IL-8 in lung tissue. Experiments were performed with a quantitative tissue-binding assay to measure the amount of 125I–IL-8 binding and an in situ tissue-binding assay to characterize the location of IL-8 binding in lung tissue. Confocal microscopy demonstrated IL-8 binding to specific anatomic locations such as cell surfaces and extracellular matrix that were enriched with heparan sulfate and chondroitin sulfate. Removal of heparan sulfate or chondroitin sulfate from lung tissue significantly decreased the binding of 125I–IL-8. Two forms of IL-8 with single amino acid mutations in the glycosaminoglycan-binding domain showed decreased binding. In addition, studies with normal and monomeric IL-8 showed that dimerization increased the binding of 125I–IL-8 in lung tissue. These findings suggest that IL-8–glycosaminoglycan interactions determine the location where IL-8 binds in lung tissue and provides a site for the dimerization of IL-8, which increases the local concentration of IL-8 in the lungs.

Abbreviations: interleukin, IL • dissociation constant, Kd • monocyte chemotactic protein, MCP • phosphate-buffered saline, PBS • polymorphonuclear neutrophils, PMN • recombinant human IL-8, rhIL-8




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