Impaired sensitivity to beta 2 integrin-blocking in ICAM-1-mediated neutrophil migration in ulcerative colitis.
BACKGROUND
Factors influencing the directed migration of neutrophils into colonic tissue in ulcerative colitis (UC) are poorly described. ICAM-1 has recently been shown to possess chemotactic properties, and the aim of this study was to evaluate the involvement of beta 2 integrins in this ICAM-1-mediated migration.


METHODS
The chemotactic effect of ICAM-1 on neutrophils isolated from 13 UC patients and 17 healthy volunteers was studied in microchemotaxis chambers. Physiological concentrations of ICAM-1 (0.05-500 pM) were separated from neutrophils by nitrocellulose filters, and cell migration was evaluated using the leading front technique. beta 2 integrins on neutrophils were blocked with antibodies to CD11a, CD11b, CD11c and CD18, and migration towards ICAM-1 was examined.


RESULTS
Migration towards ICAM-1 was equal for UC and control neutrophils, showing a bell-shaped ICAM-1 dosemigratory response curve with peak migration at 5 pM ICAM-1 (30.0 microns; interquartile range 22.9-35.7; P < 0.001). Blockade of the CD11 subunits on control cells inhibited the chemoattractant effect of ICAM-1 by 43.6%-58.0%, whereas the migration was decreased by only 20% in UC under similar blocking conditions (P < 0.01). Anti-CD18 mAbs had no effect. Inhibition of protein kinases with staurosporin only slightly decreased the ICAM-1-mediated migration, whereas incubation with staurosporin and CD11 antibodies showed additive effects on UC neutrophils and synergistic effects on control cells. No quantitative differences in beta 2 integrin expression were detected between control and UC neutrophils.


CONCLUSIONS
The chemotactic property of ICAM-1 was shown to be CD11-dependent and UC neutrophils were found to be less dependent on CD11/ICAM-1-mediated migration than were control neutrophils.
Vainer
B
B
Dept. of Medicine M, Division of Gastroenterology, Glostrup Hospital, Nordre Ringvej, DK-2600 Glostrup, Denmark. ben.vainer@dadlnet.dk
Brimnes
J
J
Claesson
M H
MH
Nielsen
O H
OH
D000328:Adult; D018845:CD11 Antigens / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003093:Colitis, Ulcerative / Q000503:physiopathology*; D005260:Female; D006801:Humans; D016023:Integrins / Q000187:drug effects*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology
D018845:CD11 Antigens; D016023:Integrins; D018799:Intercellular Adhesion Molecule-1