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CX₃C-Chemokine, Fractalkine-Enhanced Adhesion of THP-1 Cells to Endothelial Cells Through Integrin-Dependent and -Independent Mechanisms¹

Seiji Goda^*,, Toshio Imai, Osamu Yoshie, Osamu Yoneda^*, Hiroshi Inoue^*,, Yutaka Nagano^*, Toshiro Okazaki^§, Hisao Imai, Eda T. Bloom^¶, Naochika Domae^* and Hisanori Umehara^2,*

Departments of ^* Internal Medicine and Periodontology, Osaka Dental University, Hanazono-cho, Hirakata-shi, Osaka, Japan; Department of Microbiology, Kinki University School of Medicine, Ohno-Higashi, Osaka-Sayama, Osaka, Japan; ^§ Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Shogoinn-Kawara-cho, Sakyo-ku, Kyoto, Japan; and ^¶ Division of Cellular and Gene Therapies, Center for Biologics Evaluation Research, Food and Drug Administration, Bethesda, MD 20892

Leukocyte adhesion and trafficking at the endothelium requires both cellular adhesion molecules and chemotactic factors. A newly identified CX₃C chemokine, fractalkine, expressed on activated endothelial cells, plays an important role in leukocyte adhesion and migration. We examined the functional effects of fractalkine on ß₁ and ß₂ integrin-mediated adhesion using a macrophage-like cell line, THP-1 cells. In this study, we report that THP-1 cells express mRNA encoding a receptor for fractalkine, CX₃CR1, determined by Northern blotting. Scatchard analysis using fractalkine-SEAP (secreted form of placental alkaline phosphatase) chimeric proteins revealed that THP-1 cells express a single class of CX₃CR1 with a dissociation constant of 30 pM and a mean expression of 440 sites per cell. THP-1 cells efficiently adhered, in a fractalkine-dependent manner, to full-length of fractalkine immobilized onto plastic and to the membrane-bound form of fractalkine expressed on ECV304 cells or TNF--activated HUVECs. Moreover, soluble-fractalkine enhanced adhesion of THP-1 cells to fibronectin and ICAM-1 in a dose-dependent manner. Pertussis toxin, an inhibitor of G_i, inhibited the fractalkine-mediated enhancement of THP-1 cell adhesion to fibronectin and ICAM-1. Finally, we found that soluble-fractalkine also enhanced adhesion of freshly separated monocytes to fibronectin and ICAM-1. These results indicate that fractalkine may induce firm adhesion between monocytes and endothelial cells not only through an intrinsic adhesion function itself, but also through activation of integrin avidity for their ligands.