GAS6 INHIBITS GRANULOCYTE ADHESION TO ENDOTHELIAL-CELLS

GAS6 is a ligand for the tyrosine kinase receptors Rse, Arl, and Mer, but its function is poorly understood. Previous studies reported that both GAS6 and Axl are expressed by vascular endothelial cells (EC), wh ich play a key role in leukocyte extravasation into tissues during inf lammation through adhesive interactions with these cells. The aim of t his work was to evaluate the GAS6 effect on the adhesive function of E C. Treatment of EC with GAS6 significantly inhibited adhesion of polym orphonuclear cells (PMN) induced by phorbol 12-myristate 13-acetate (P MA), platelet-activating factor (PAF), thrombin, interleukin-1 beta (I L-1 beta) and tumor necrosis factor-alpha (TNF-alpha), but not that in duced by FMLP and IL-8. GAS6 did not affect adhesion to resting EC. Ti tration experiments showed that high concentrations of GAS6 were neede d to inhibit PMN adhesion and that inhibition was dose-dependent at th e concentration range of 0.1 to 1 mu g/mL. One possibility was that hi gh concentrations were needed to overwhelm the effect of endogenous GA S6 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 an alysis showed that it is concentrated along the plasma membrane in res ting EC and treatment with PAF induces depletion and/or redistribution of the molecule. These data suggest that GAS6 functions as a physiolo gic antiinflammatory agent produced by resting EC and depleted when pr oinflammatory stimuli turn on the proadhesive machinery of EC. (C) 199 8 by The American Society of Hematology.