Glycosaminoglycan Binding and Oligomerization Are Essential for the in vivo Activity of Certain Chemokines

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 4; pp. 1885 - 1890
• Main Authors: Amanda E. I. Proudfoot, Handel, Tracy M., Johnson, Zoë, Lau, Elaine K., LiWang, Patricia, Clark-Lewis, Ian, Borlat, Frédéric, Timothy N. C. Wells, Kosco-Vilbois, Marie H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.02.2003; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; Base Sequence; Binding Sites; Biochemistry; Biological Sciences; Biopolymers; Cells; Chemokines; Chemokines - metabolism; Chemokines - physiology; Chemotaxis; Chemotaxis, Leukocyte; CHO Cells; Cricetinae; Dimers; DNA Primers; Female; Glycosaminoglycans; Glycosaminoglycans - chemistry; Glycosaminoglycans - metabolism; Heparin; Immunology; In Vitro Techniques; Ligands; Mice; Mice, Inbred BALB C; Peritoneal Cavity - cytology; Receptors; Recombinant Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0334864100

During organogenesis, immunosurveillance, and inflammation, chemokines selectively recruit leukocytes by activating seven-transmembrane-spanning receptors. It has been suggested that an important component of this process is the formation of a haptotactic gradient by immobilization of chemokines on cell surface glycosaminoglycans (GAGs). However, this hypothesis has not been experimentally demonstrated in vivo. In the present study we investigated the effect of mutations in the GAG binding sites of three chemokines, monocyte chemoattractant protein-1/CC chemokine ligand (CCL)2, macrophage-inflammatory protein-1β/CCL4, and RANTES/CCL5, on their ability to recruit cells in vivo. These mutant chemokines retain chemotactic activity in vitro, but they are unable to recruit cells when administered intraperitoneally. Additionally, monomeric variants, although fully active in vitro, are devoid of activity in vivo. These data demonstrate that both GAG binding and the ability to form higher-order oligomers are essential for the activity of particular chemokines in vivo, although they are not required for receptor activation in vitro. Thus, quaternary structure of chemokines and their interaction with GAGs may significantly contribute to the localization of leukocytes beyond migration patterns defined by chemokine receptor interactions.