GAS6 inhibits granulocyte adhesion to endothelial cells.
GAS6 is a ligand for the tyrosine kinase receptors Rse, Axl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), which play a key role in leukocyte extravasation into tissues during inflammation through adhesive interactions with these cells. The aim of this work was to evaluate the GAS6 effect on the adhesive function of EC. Treatment of EC with GAS6 significantly inhibited adhesion of polymorphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (PMA), platelet-activating factor (PAF), thrombin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), but not that induced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Titration experiments showed that high concentrations of GAS6 were needed to inhibit PMN adhesion and that inhibition was dose-dependent at the concentration range of 0.1 to 1 microg/mL. One possibility was that high concentrations were needed to overwhelm the effect of endogenous GAS6 produced by EC. In line with this possibility, treatment of resting EC with soluble Axl significantly potentiated PMN adhesion. Analysis of localization of GAS6 by confocal microscopy and cytofluorimetric analysis showed that it is concentrated along the plasma membrane in resting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiologic antiinflammatory agent produced by resting EC and depleted when proinflammatory stimuli turn on the proadhesive machinery of EC.
Avanzi
G C
GC
Dipartimento di Scienze Mediche, Universita di Torino, Torino, Italy.
Gallicchio
M
M
Bottarel
F
F
Gammaitoni
L
L
Cavalloni
G
G
Buonfiglio
D
D
Bragardo
M
M
Bellomo
G
G
Albano
E
E
Fantozzi
R
R
Garbarino
G
G
Varnum
B
B
Aglietta
M
M
Saglio
G
G
Dianzani
U
U
Dianzani
C
C
D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000494:pharmacology; D000074428:Peroxisomal Biogenesis Factor 2; D011506:Proteins / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000099255:Growth Arrest-Specific Protein 6
D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000074428:Peroxisomal Biogenesis Factor 2; D011506:Proteins; D013755:Tetradecanoylphorbol Acetate; D000099255:Growth Arrest-Specific Protein 6