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J Immunol. 2014 Apr 15;192(8):3908-3914. doi: 10.4049/jimmunol.1302159. Epub 2014 Mar 17.

Chemokine cooperativity is caused by competitive glycosaminoglycan binding.

Author information

1
Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
2
Merck Research Laboratories, Molecular Pharmacology & DMPK, Oss, The Netherlands.
3
Department of Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA, USA.
5
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
6
Merck Serono Geneva Research Centre, Geneva, Switzerland.
7
Netherlands Translational Research Center B.V. (NTRC), Oss, The Netherlands.
#
Contributed equally

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.

PMID:
24639348
PMCID:
PMC4198333
DOI:
10.4049/jimmunol.1302159
[Indexed for MEDLINE]
Free PMC Article

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