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A small‐molecule antagonist of LFA‐1 blocks a conformational change important for LFA‐1 function
Author(s) -
Woska Joseph R.,
Shih Dawtsun,
Taqueti Viviany R.,
Hogg Nancy,
Kelly Terence A.,
Kishimoto Takashi K.
Publication year - 2001
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.70.2.329
Subject(s) - lymphocyte function associated antigen 1 , biology , microbiology and biotechnology , receptor , small molecule , monoclonal antibody , biophysics , epitope , intracellular , in vitro , intercellular adhesion molecule 1 , antigen , biochemistry , antibody , immunology
Lymphocyte function‐associated antigen(LFA)‐1/intercellular adhesion molecule (ICAM)‐1interactions mediate several important steps in the evolution of animmune response. LFA‐1 is normally expressed in a quiescent state onthe surface of leukocytes and interacts weakly with its ligands ICAM‐1,‐2, and ‐3. LFA‐1 activity may be regulated by receptor clustering andby increasing the affinity of LFA‐1 for its ligands. Affinitymodulation of LFA‐1 has been shown to occur via a conformational changein the LFA‐1 heterodimer that can be detected by using monoclonalantibody 24 (mAb24). We have recently described a small‐moleculeantagonist of LFA‐1, BIRT 377, that demonstrates selective in vitro andin vivo inhibition of LFA‐1/ICAM‐1‐mediated binding events. We nowdemonstrate that BIRT 377 blocks the induction of the mAb24 reporterepitope on LFA‐1 on the surface of SKW‐3 cells treated with variousagonists known to induce high‐affinity LFA‐1. These data imply thatBIRT 377 exerts its inhibitory effects by preventing up‐regulation ofLFA‐1 to its high‐affinity conformation.