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VOL. 74 (4) SIGNALS EMANATING FROM LEUKOCYTE...

is essential for the formation and stability of the focal zone and for LFA-
1-dependent migration (61).

SIGNALS TRIGGERED BY ENDOTHELIAL RECEPTORS UPON
INTEGRIN ENGAGEMENT

VCAM-1 and ICAM-1, members of the Ig superfamily, are the
two major endothelial adhesion molecules involved in the binding to the
main leukocyte integrins VLA-4 and LFA-1, respectively (62, 63).
ICAM-1 but not VCAM-1 is expressed at low levels in resting
endothelium, and both molecules are induced upon cell activation by pro-
inflammatory cytokines such as IL-1 and TNF-a (64, 65).

Endothelium is no longer considered as a passive barrier during
Transendothelial Migration (TEM). In fact, endothelial cells form
“docking” structures to firmly attach leukocytes upon the binding of
VCAM-1 and ICAM-1 to their respective leukocyte ligands, VLA-4 and
LFA-1. These cup-like structures are based on microvilli that emerge
from the endothelial apical surface and their essential constituents include
endothelial adhesion receptors, together with the actin cytoskeleton,
adaptor proteins (ERM, alpha-actinin, vinculin, VASP) and signaling
molecules (PIP2, Rho/ROCK) (66). The relevant role of these structures
for leukocyte adhesion and transmigration has been unveiled in
experiments under flow conditions (66).

VCAM-1 and ICAM-1 are capable of transducing signals after
ligand binding, that cooperate to increase endothelial permeability and
facilitate leukocyte transmigration (67, 68). VCAM-1 is involved in the
opening of the “endothelial passage” through which leukocytes can
extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase
activation and the production of reactive oxygen species (ROS) in a Rac-
mediated manner, with subsequent activation of matrix
metalloproteinases and loss of VE-cadherin-mediated adhesion. This
signaling pathway can be blocked by TGFbeta1 and IFNgamma (69-72).
On the other hand, cross-linking of both VCAM-1 and ICAM-1 induces a
rapid increase in intracellular Ca2+ concentration (28, 73). ICAM-1-
mediated calcium increase triggers activation of Src and subsequent

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