title: Heparin displaces interferon-gamma-inducible chemokines (IP-10, I-TAC, and Mig) sequestered in the vasculature and inhibits the transendothelial migration and arterial recruitment of T cells.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, Conn, USA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Ranjbaran
authors.forename: Yinong
authors.initials: Y
authors.lastname: Wang
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Manes
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Yakimov
authors.forename: Shamsuddin
authors.initials: S
authors.lastname: Akhtar
authors.forename: Martin S
authors.initials: MS
authors.lastname: Kluger
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: George
authors.initials: G
authors.lastname: Tellides
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D018925:Chemokines / Q000378:metabolism*; D019743:Chemokines, CXC / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006493:Heparin / Q000378:metabolism* / Q000494:pharmacology*; D006494:Heparin Antagonists / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D011479:Protamines / Q000494:pharmacology; D011485:Protein Binding; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; C515188:Cxcr3 protein, mouse; D006494:Heparin Antagonists; D011479:Protamines; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D018664:Interleukin-12; D007371:Interferon-gamma; D006493:Heparin