Low-Molecular-Weight Heparins Inhibit CCL21-Induced T Cell Adhesion and Migration
- Departments of 1(K.W.C., R.A.H)Biochemistry/Molecular Biology and Hematology/Oncology, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana; 2(J.J.C.)Joint Program in Transfusion Medicine, Children's Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts; and 3(J.B.T)Department of Dermatology, Wells Center for Pediatric Research, and Riley Hospital for Children, Indianapolis, Indiana
- Dr. Robert A. Hromas, 1044 W. Walnut St., Indianapolis, IN 46202. E-mail: rhromas{at}iupui.edu
Abstract
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.
Footnotes
- Abbreviations:
- ICAM-1
- intercellular adhesion molecule-1
- GAG
- glycosaminoglycan
- MIP
- macrophage inflammatory protein
- APTT
- activated partial thromboplastin times
- CCR7
- chemokine receptor-7
- LMW
- low molecular weight
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- Received September 26, 2001.
- Accepted March 8, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
