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Alan M. Fong^*, Lisa A. Robinson^,, Douglas A. Steeber, Thomas F. Tedder, Osamu Yoshie^||, Toshio Imai^||, and Dhavalkumar D. Patel^*,

From the ^* Department of Medicine, the Department of Immunology, and the Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710; and the ^|| Shionogi Institute for Medical Science, Settsu 566, Japan

Leukocyte migration into sites of inflammation involves multiple molecular interactions between leukocytes and vascular endothelial cells, mediating sequential leukocyte capture, rolling, and firm adhesion. In this study, we tested the role of molecular interactions between fractalkine (FKN), a transmembrane mucin-chemokine hybrid molecule expressed on activated endothelium, and its receptor (CX₃CR1) in leukocyte capture, firm adhesion, and activation under physiologic flow conditions. Immobilized FKN fusion proteins captured resting peripheral blood mononuclear cells at physiologic wall shear stresses and induced firm adhesion of resting monocytes, resting and interleukin (IL)-2–activated CD8⁺ T lymphocytes and IL-2–activated NK cells. FKN also induced cell shape change in firmly adherent monocytes and IL-2–activated lymphocytes. CX₃CR1-transfected K562 cells, but not control K562 cells, firmly adhered to FKN-expressing ECV-304 cells (ECV-FKN) and tumor necrosis factor –activated human umbilical vein endothelial cells. This firm adhesion was not inhibited by pertussis toxin, EDTA/EGTA, or antiintegrin antibodies, indicating that the firm adhesion was integrin independent. In summary, FKN mediated the rapid capture, integrin-independent firm adhesion, and activation of circulating leukocytes under flow. Thus, FKN and CX₃CR1 mediate a novel pathway for leukocyte trafficking.

Key Words: leukocyte migration • chemokines • cell adhesion • fractalkine • chemokine receptors

A.M. Fong and L.A. Robinson contributed equally to this work.

Abbreviations used: ELC, EBI1 ligand chemokine; FKN, fractalkine; HUVECs, human umbilical vein endothelial cells; IF, immunofluorescence; MCP, monocyte chemotactic protein; PTX, pertussis toxin; SEAP, secreted placental alkaline phosphatase; TARC, thymus and activation regulated chemokine.

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