Low-molecular-weight heparins inhibit CCL21-induced T cell adhesion and migration.
The chemokine CCL21, also known as Exodus-2/6-Ckine/secondary lymphoid-tissue chemokine/T cell activator protein-4, is the most potent stimulator of T cell migration and adhesion yet described. Endothelial heparin-like glycosaminoglycans (GAGs) are thought to present chemokines at sites of inflammation, maintaining a local concentration gradient to which leukocytes can respond. In contrast, this study found that GAGs markedly inhibit the ability of CCL21 to stimulate T cell adhesion and chemotaxis. Enzymes, such as heparinase, that split GAGs into component-sulfated saccharides abrogate this inhibition, suggesting a mechanism for local tissue regulation of CCL21 function. Low-molecular-weight heparins also strongly inhibit CCL21 adhesion and chemotaxis. Therefore, low-molecular-weight heparins may be effective therapeutic agents in decreasing the pathology of T cell-infiltrative autoimmune diseases by targeting the CCL21 regulation of T cell infiltration.
Christopherson
Kent W
KW
Department of Biochemistry/Molecular Biology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Campbell
James J
JJ
Travers
Jeffrey B
JB
Hromas
Robert A
RA
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000494:pharmacology; D019763:Heparin Lyase / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D013601:T-Lymphocytes / Q000187:drug effects*
D020533:Angiogenesis Inhibitors; D000925:Anticoagulants; C515478:CCL21 protein, human; D054421:Chemokine CCL21; D019742:Chemokines, CC; D006025:Glycosaminoglycans; D006495:Heparin, Low-Molecular-Weight; D019763:Heparin Lyase