Heparin displaces interferon-γ-inducible chemokines (IP-10, I-TAC, and mig) sequestered in the vasculature and inhibits the transendothelial migration and arterial recruitment of T cells

• Published in: Circulation (New York, N.Y.) Vol. 114; no. 12; pp. 1293 - 1300
• Main Authors: RANJBARAN, Hooman, YINONG WANG, MANES, Thomas D, YAKIMOV, Alexander O, AKHTAR, Shamsuddin, KLUGER, Martin S, POBER, Jordan S, TELLIDES, George
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 19.09.2006
• Subjects: Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Cell Movement - drug effects; Cells, Cultured; Chemokine CXCL10; Chemokine CXCL11; Chemokine CXCL9; Chemokines - metabolism; Chemokines, CXC - metabolism; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Coronary Vessels - pathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Fundamental and applied biological sciences. Psychology; Heparin - metabolism; Heparin - pharmacology; Heparin Antagonists - pharmacology; Humans; Interferon-gamma - metabolism; Interleukin-12 - metabolism; Medical sciences; Pharmacology. Drug treatments; Protamines - pharmacology; Protein Binding; Receptors, Chemokine - drug effects; Receptors, Chemokine - metabolism; Receptors, CXCR3; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Th1 Cells - metabolism; Th1 Cells - pathology; Vertebrates: cardiovascular system; lymphocytes; C chemokine; Cytokine; Cardiovascular disease; Anticoagulant; Inflammation; chemokines; Endothelium; T-Lymphocyte; Glycosaminoglycan; Interferon; Heparin; CXC chemokine
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.106.631457

Heparin, used clinically as an anticoagulant, also has antiinflammatory properties and has been described to inhibit interferon (IFN)-gamma responses in endothelial cells. We investigated the effects of heparin on the IFN-gamma-inducible chemokines IP-10/CXCL10, I-TAC/CXCL11, and Mig/CXCL9, which play important roles in the vascular recruitment of IFN-gamma-producing Th1 cells through interactions with their cognate receptor, CXCR3. Patients undergoing coronary artery bypass grafting were studied because coronary atherosclerosis is recognized as a Th1-type inflammatory disease and the subjects required systemic heparinization. Plasma levels of IP-10, I-TAC, and Mig increased immediately after heparin administration and diminished promptly after heparin antagonism with protamine. These effects were independent of detectable circulating IFN-gamma or the IFN-gamma inducer interleukin-12. We confirmed previous reports that heparin inhibits the IFN-gamma-dependent production of CXCR3 chemokine ligands using atherosclerotic coronary arteries in organ culture. In addition to prolonged treatment decreasing chemokine secretion, heparin rapidly displaced membrane-associated IP-10 from cultured endothelial cells that did not express CXCR3 and reduced the IP-10-dependent transendothelial migration of T helper cells under conditions of venular shear stress. Finally, heparin administration to immunodeficient mouse hosts decreased both the recruitment and accumulation of memory T cells within allogeneic human coronary arteries. Besides inhibiting IFN-gamma responses, heparin has further immunomodulatory effects by competing for binding with IP-10, I-TAC, and Mig on endothelial cells. Disruption of CXCR3+ Th1 cell trafficking to arteriosclerotic arteries may contribute to the therapeutic efficacy of heparin in inflammatory arterial diseases, and nonanticoagulant heparin derivatives may represent a novel antiinflammatory strategy.