title: Chemokine cooperativity is caused by competitive glycosaminoglycan binding.
abstract: Chemokines comprise a family of secreted proteins that activate G protein-coupled chemokine receptors and thereby control the migration of leukocytes during inflammation or immune surveillance. The positional information required for such migratory behavior is governed by the binding of chemokines to membrane-tethered glycosaminoglycans (GAGs), which establishes a chemokine concentration gradient. An often observed but incompletely understood behavior of chemokines is the ability of unrelated chemokines to enhance the potency with which another chemokine subtype can activate its cognate receptor. This phenomenon has been demonstrated to occur between many chemokine combinations and across several model systems and has been dubbed chemokine cooperativity. In this study, we have used GAG binding-deficient chemokine mutants and cell-based functional (migration) assays to demonstrate that chemokine cooperativity is caused by competitive binding of chemokines to GAGs. This mechanistic explanation of chemokine cooperativity provides insight into chemokine gradient formation in the context of inflammation, in which multiple chemokines are secreted simultaneously.
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.|Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.|Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
authors.forename: Jody
authors.initials: J
authors.lastname: van Offenbeek
authors.affiliation: Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
authors.forename: Miranda M C
authors.initials: MMC
authors.lastname: van der Lee
authors.affiliation: Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
authors.forename: Lambertus H C J
authors.initials: LHCJ
authors.lastname: van Lith
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Anne O
authors.initials: AO
authors.lastname: Watts
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Angelique L W M M
authors.initials: ALWMM
authors.lastname: Rops
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Aguilar
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Ziarek
authors.affiliation: Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA, USA.
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Handel
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Volkman
authors.affiliation: Merck Serono Geneva Research Centre, Geneva, Switzerland.
authors.forename: Amanda E I
authors.initials: AEI
authors.lastname: Proudfoot
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Vischer
authors.affiliation: Netherlands Translational Research Center B.V. (NTRC), Oss, The Netherlands.
authors.forename: Guido J R
authors.initials: GJR
authors.lastname: Zaman
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D054415:Chemokine CCL19 / Q000378:metabolism; D054421:Chemokine CCL21 / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000378:metabolism; D018925:Chemokines / Q000737:chemistry / Q000378:metabolism*; D002633:Chemotaxis; D006224:Cricetinae; D003412:Cricetulus; D006025:Glycosaminoglycans / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding; D055503:Protein Multimerization; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D018925:Chemokines; D006025:Glycosaminoglycans; D019707:Receptors, Chemokine