title: Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines.
abstract: 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-1beta/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.
authors.affiliation: Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland. amanda.proudfoot@serono.com
authors.forename: Amanda E I
authors.initials: AE
authors.lastname: Proudfoot
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
authors.forename: Zoë
authors.initials: Z
authors.lastname: Johnson
authors.forename: Elaine K
authors.initials: EK
authors.lastname: Lau
authors.forename: Patricia
authors.initials: P
authors.lastname: LiWang
authors.forename: Ian
authors.initials: I
authors.lastname: Clark-Lewis
authors.forename: Frédéric
authors.initials: F
authors.lastname: Borlat
authors.forename: Timothy N C
authors.initials: TN
authors.lastname: Wells
authors.forename: Marie H
authors.initials: MH
authors.lastname: Kosco-Vilbois
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D001704:Biopolymers; D016466:CHO Cells; D018925:Chemokines / Q000378:metabolism / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D006224:Cricetinae; D017931:DNA Primers; D005260:Female; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D010529:Peritoneal Cavity / Q000166:cytology; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D001704:Biopolymers; D018925:Chemokines; D017931:DNA Primers; D006025:Glycosaminoglycans; D011994:Recombinant Proteins