Intercellular adhesion molecule-1 dimerization and its consequences for adhesion mediated by lymphocyte function associated-1.

Abstract

SummaryIntercellular adhesion molecule-1 (ICAM-1, CD54) is a ligand for the integrins lymphocyte function associated-1 (LFA-1, CD11a/CD18) and complement receptor-3 (Mac-l, CD11b/ CD 18) making it an important participant in many immune and inflammatory processes. Modified recombinant soluble ICAM-1 formed dimers. This result indicated that the ectodomain of ICAM-1 contains homophilic interaction sites. Soluble ICAM-1 dimers bind to solid-phase purified LFA-I with high avidity (dissociation constant [Ka] = 8 nM) in contrast to soluble ICAM-1 monomers whose binding was not measurable. Cell surface ICAM-1 was found to be dimeric based on two distinct criteria. First, a monoclonal antibody specific for monomeric soluble ICAM-1, CA7, binds normal ICAM-1 poorly at the cell surface; this antibody, however, binds strongly to two mutant forms of [CAM-1 when expressed at the cell surface, thus identifying elements required for dimer formation. Second, chemical cross-linking of cell surface ICAM-1 on transfected cells and tumor necrosis factor-activated endothelial cells results in conversion of a portion oflCAM-1 to a covalent dimer. Cell surface ICAM-1 dimers are more potent ligands for LFA-l-dependent adhesion than ICAM-1 monomers. While many extracellular matrix-associated ligands of integrins are multimeric, this is the first evidence of specific, functionally important homodimerization of a cell surface integrin ligand.

RKIKK Motif in the Intracellular Domain Is Critical for Spatial and Dynamic Organization of ICAM-1: Functional Implication for the Leukocyte Adhesion and Transmigration

“…ICAM-1 appears to exist as a dimer or higher multimers in its native state on the cell surface, as shown by cross-linking studies (Miller et al, 1995;Reilly et al, 1995), and it has been postulated that the multimeric form of ICAM-1 mediates better adhesion to LFA-1. However, the relative importance of the topographical distribution of ICAM-1 in connecting with its function to mediate leukocyte transmigration has been less extensively investigated.…”

The role of ICAM-1 on T-cells in the pathogenesis of asthma

“…We present here early attempts to interfere with intercellular adhesion molecule-1 as an adhesion molecule involved in cell influx and studies aimed preventing virus-induced exacerbations of asthma in children based on the knowledge that intercellular adhesion molecule-1 is the receptor for rhinoviruses. Eur Respir J 1998;11: 949-957. molecules [5]. Endothelial ICAM-1 is up-regulated at the site of inflammation by a host of cytokines.…”

“…The monomeric forms of sICAM-1 bind to the receptor LFA-1 with extremely low affinity [5]. It has been found that the levels of dimerization of ICAM-1 shed in vitro directly correlate with enhanced binding to LFA-1 [5,67].…”

“…It has been found that the levels of dimerization of ICAM-1 shed in vitro directly correlate with enhanced binding to LFA-1 [5,67]. Multimeric forms of ICAM-1, shed from the cell surface and concentrated at sites of inflammation, may bind to LFA-1 with sufficient affinity to interfere with the local immune response [66].…”

Procalcitonin, C-Reactive Protein, Interleukin-6, and Soluble Intercellular Adhesion Molecule-1 as Markers of Postoperative Orthopaedic Joint Prosthesis Infections

“…Its soluble forms (sICAM-1), both monomeric and dimeric, are generated by proteolytic cleavage (16)(17)(18)(19). The majority of molecules that bind ICAM-l are leukocyte integrins (LFA-l and Mac-) (20)(21)(22)(23), but also other types of molecules, including fibrinogen, rhinoviruses, and erythrocytes infected by Plasmodium falciparum can bind this molecule (24)(25).…”