Fractalkine-mediated endothelial cell injury by NK cells

Endothelial cells (ECs) are primary targets of immunological attack, and th eir injury can lead to vasculopathy and organ dysfunction in vascular leak syndrome and in rejection of allografts or xenografts, A newly identified C X3C-chemokine, fractalkine, expressed on activated ECs plays an important r ole in leukocyte adhesion and migration. In this study we examined the func tional roles of fractalkine on NK cell activity and NK cell-mediated endoth elial cell injury. Freshly separated NK cells expressed the fractalkine rec eptor (CX(3)CR1) determined by FAGS analysis and efficiently adhered to imm obilized full-length fractalkine, but not to the truncated forms of the che mokine domain or mucin domain, suggesting that fractalkine functions as an adhesion molecule on the interaction between NK cells and ECs, Soluble frac talkine enhanced NK cell cytolytic activity against K562 target cells in a dose- and time-dependent manner, This enhancement correlated well with incr eased granular exocytosis from NK cells, which nas completely inhibited by the G protein inhibitor, pertussis toxin, Transfection of fractalkine cDNA into ECV304 cells or HUVECs resulted in increased adhesion of NK cells and susceptibility to NK cell-mediated cytolysis compared with control transfec tion, Moreover, both enhanced adhesion and susceptibility of fractalkine-tr ansfected cells were markedly suppressed by soluble fractalkine or anti-CX( 3)CR1 Ab, Our results suggest that fractalkine plays an important role not only in the binding of NK cells to endothelial cells, but also in NK cell-m ediated endothelium damage, which may result in vascular injury.