Fractalkine-mediated endothelial cell injury by NK cells.
Endothelial cells (ECs) are primary targets of immunological attack, and their injury can lead to vasculopathy and organ dysfunction in vascular leak syndrome and in rejection of allografts or xenografts. A newly identified CX3C-chemokine, fractalkine, expressed on activated ECs plays an important role in leukocyte adhesion and migration. In this study we examined the functional roles of fractalkine on NK cell activity and NK cell-mediated endothelial cell injury. Freshly separated NK cells expressed the fractalkine receptor (CX3CR1) determined by FACS analysis and efficiently adhered to immobilized full-length fractalkine, but not to the truncated forms of the chemokine domain or mucin domain, suggesting that fractalkine functions as an adhesion molecule on the interaction between NK cells and ECs. Soluble fractalkine enhanced NK cell cytolytic activity against K562 target cells in a dose- and time-dependent manner. This enhancement correlated well with increased granular exocytosis from NK cells, which was 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 transfection. Moreover, both enhanced adhesion and susceptibility of fractalkine-transfected cells were markedly suppressed by soluble fractalkine or anti-CX3CR1 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-mediated endothelium damage, which may result in vascular injury.
Yoneda
O
O
Department of Internal Medicine, Department of Periodontology, Osaka Dental University, Osaka, Japan.
Imai
T
T
Goda
S
S
Inoue
H
H
Yamauchi
A
A
Okazaki
T
T
Imai
H
H
Yoshie
O
O
Bloom
E T
ET
Domae
N
N
Umehara
H
H
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005089:Exocytosis / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D018121:Receptors, Cytokine / Q000096:biosynthesis; D015728:Receptors, HIV / Q000096:biosynthesis; D012995:Solubility; D014162:Transfection
D000276:Adjuvants, Immunologic; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D019743:Chemokines, CXC; D008565:Membrane Proteins; D018121:Receptors, Cytokine; D015728:Receptors, HIV