Heparin regulates ICAM-1 expression in human endothelial cells: an example of non-cytokine-mediated endothelial activation.
Activated endothelial cells up-regulate the expression of several molecules on their plasma membranes, including intercellular adhesion molecule-1 (ICAM-1). The role of heparin in regulating endothelial cell gene expression is unclear. We thus have investigated the ability of heparin to regulate ICAM- gene expression by using flow cytometry and the ribonuclease protection assay with human umbilical vein and aortic endothelial cells cultured in growth medium supplemented with 90 [microg/ml heparin (heparin-sufficient, HS) or in growth medium without added heparin (heparin-deficient, HD). We found that HD medium increased plasma membrane protein and mRNA for ICAM-1 but not for HLA-DR, even though both ICAM-1 and HLA-DR protein and mRNA were inducible by gamma interferon (IFN-gamma). In addition, phorbol ester and IFN-gamma increased the expression of plasma membrane ICAM-1 or ICAM-1 and HLA-DR, respectively, more in HD medium than in HS medium. We found that the HD-mediated increase of ICAM- mRNA was reversible by the addition of heparin, and that the half-life of ICAM-1 mRNA was the same in both HS- and HD-treated cells. Also, heparin was found to suppress increases in ICAM-1 mRNA at a concentration as low as 5 microg/ml. These findings indicate that heparin deficiency induces endothelial activation characterized by increased ICAM-1, and that such induction is not dependent on cytokines or endotoxin. The modulation of ICAM-1 expression by heparin appears to occur at the transcriptional level. Thus, heparin may have a role in regulating endothelial function by affecting the expression of ICAM-1, thereby impacting upon the trans-endothelial trafficking of leukocytes.
Division of Experimental Pathology, Methodist Research Institute, Inc., Indianapolis, Indiana 46202, USA. sjmiller@hotmail.com
S J
SJ
Miller
A M
AM
Hoggat
W P
WP
Faulk
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*
D005343:Fibrinolytic Agents; D006684:HLA-DR Antigens; D018799:Intercellular Adhesion Molecule-1; D006493:Heparin