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1 Department of Physiology and Biophysics, University of Miami School of Medicine,, Miami, FL, USA
2 Department of Pediatrics, State University of New York, Stony Brook, Stony Brook, NY, USA
3 Department of Medicine, State University of New York, Stony Brook, Stony Brook, NY, USA
4 Department of Medicine, The University of Tokyo, Tokyo, Japan
5 Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: michael_goligorsky{at}nymc.edu.
Leukocyte adhesion to vascular endothelium is a key initiating step in the pathogenesis of many inflammatory diseases. Here we present real-time force measurements of the interaction between monocytic HL-60 cells and a monolayer of human umbilical vein endothelial cells (HUVECs) using atomic force microscopy (AFM). The detachment of HL-60/HUVEC conjugates involved a series of
rupture events with force transitions of 40-100 pN. The integrated force of these rupture events provided a quantitative measure of the adhesion strength on a whole cell level. The AFM measurements revealed that HL-60 adhesion is heightened in the borders formed by adjacent
HUVECs. The average force and mechanical work required to detach a single HL-60 from the borders of a TNF-alpha activated HUVEC layer were twice as high as those of the HUVEC bodies. HL-60 adhesion to the monolayer was significantly reduced by a monoclonal antibody against 
1 integrins, and partially inhibited by antibodies against selectins, ICAM-1 and VCAM-1, but was not affected by anti-
V3. Interestingly, adhesion was also inhibited in a dose dependent manner (IC50
100nM) by a cyclic Arginine-Glycine-Aspartic Acid (cRGD) peptide. This effect was mediated via interfering with the VLA-4-VCAM-1 binding. In parallel measurements, transmigration of HL-60 cells across a confluent HUVEC monolayer was inhibited by the cRGD peptide, and by both anti-1 and anti-V3 antibodies. In conclusion, these data demonstrate the role played by 1 integrins in leukocyteendothelial adhesion and transmigration and the role played by V3 in transmigration, thus underscoring the high efficacy of cRGD peptide in blocking both the adhesion and transmigration of monocytes.
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