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The Journal of Immunology, 2001, 167: 3099-3106.
Copyright © 2001 by The American Association of Immunologists

Human Endothelial-Cell Specific Molecule-1 Binds Directly to the Integrin CD11a/CD18 (LFA-1) and Blocks Binding to Intercellular Adhesion Molecule-11

David Béchard*, Arnaud Scherpereel*, Hamida Hammad*, Thibaut Gentina*, Anne Tsicopoulos*, Marc Aumercier{dagger}, Jöel Pestel*, Jean-Paul Dessaint{ddagger}, André-Bernard Tonnel* and Philippe Lassalle2,*

* Institut National de la Santé et de la Recherche Médicale Unité 416, Institut Pasteur de Lille; {dagger} Centre National de la Recherche Scientifique Unité Mixte de Recherche 8526, Institut de Biologie de Lille; and {ddagger} Laboratoire d’Immunologie, Centre Hospitalier Régional Universitaire, Lille, France

ICAMs are ligands for LFA-1, a major integrin of mononuclear cells involved in the immune and inflammatory processes. We previously showed that endothelial cell specific molecule-1 (ESM-1) is a proteoglycan secreted by endothelial cells under the control of inflammatory cytokines. Here, we demonstrate that ESM-1 binds directly to LFA-1 onto the cell surface of human blood lymphocytes, monocytes, and Jurkat cells. The binding of ESM-1 was equally dependent on Ca2+, Mg2+, or Mn2+ divalent ions, which are specific, saturable, and sensitive to temperature. An anti-CD11a mAb or PMA induced a transient increase in binding, peaking 5 min after activation. Direct binding of ESM-1 to LFA-1 integrin was demonstrated by specific coimmunoprecipitation by CD11a and CD18 mAbs. A cell-free system using a Biacore biosensor confirmed that ESM-1 and LFA-1 dynamically interacted in real time with high affinity (Kd = 18.7 nM). ESM-1 consistently inhibited the specific binding of soluble ICAM-1 to Jurkat cells in a dose-dependent manner. These results suggest that ESM-1 and ICAM-1 interact with LFA-1 on binding sites very close to but distinct from the I domain of CD11a. Through this mechanism, ESM-1 could be implicated in the regulation of the LFA-1/ICAM-1 pathway and may therefore influence both the recruitment of circulating lymphocytes to inflammatory sites and LFA-1-dependent leukocyte adhesion and activation.




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