title: Chondroitin sulfate A released from platelets blocks RANTES presentation on cell surfaces and RANTES-dependent firm adhesion of leukocytes.
abstract: The sequestration of chemokines on the surface of microvascular endothelium is an early event in the selective recruitment of leukocytes. The sequestration and presentation of chemokines must be tightly controlled to confine the extravasation of leukocytes and to prevent uncontrolled inflammation. We investigated whether soluble molecules released under physiological conditions could control chemokine immobilization on cell surfaces and function as regulatory chemokine binding molecules. We determined that human serum contains a molecule that suppresses RANTES (CCL5) binding to endothelial cells, PBMC and CHO cells. Using platelet-rich and platelet-free plasma, serum from patients with thrombocytopenia, and purified platelets, we identified platelets as the source of the chemokine-binding molecule and further identified it as chondroitin sulfate A. In contrast to platelet-derived fully-sulfated chondroitin sulfate A, low-sulfated chondroitin sulfate A present in plasma was almost inactive. Under physiological flow conditions chondroitin sulfate A was found to block RANTES-mediated firm adhesion of monocytes to endothelial cells. It also prevented RANTES-mediated influx of calcium in CCR5-transfected CHO cells while internalization of CCR5 was only marginally reduced. Taken together, chondroitin sulfate A released from platelets appears to act as an important regulatory molecule for cellular responses to chemokines.
authors.affiliation: Medical Policlinic, University of Munich, Munich, Germany. mack@medpoli.med.uni-muenchen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.forename: Jochen
authors.initials: J
authors.lastname: Pfirstinger
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Kim S C
authors.initials: KS
authors.lastname: Weber
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.forename: Tamara
authors.initials: T
authors.lastname: Rupp
authors.forename: Konstantin
authors.initials: K
authors.lastname: Maletz
authors.forename: Hilke
authors.initials: H
authors.lastname: Brühl
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism*; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000097:blood / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004492:Edetic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019713:Receptors, CCR5; D019707:Receptors, Chemokine / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection
chemical_list: D002614:Chelating Agents; D018946:Chemokine CCL5; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D002809:Chondroitin Sulfates; D004492:Edetic Acid; D002118:Calcium