Topic 2 lecture note..

neutrophil transmigration through cytokine activated endothelium by 70-90%. Binding of
leukocytes to endothelium is not affected. Although V3 integrin can be a ligand for
PECAM-1, and monocytes lacking 3-integrin transmigrate poorly, this appears to be
due to modulation of CD11a/CD18 rather than by an interaction with PECAM-1. In
contrast to cytokine-activated transmigration, PECAM-1 seems to have little role in
chemotactic transmigration. PECAM-1 antibodies do not decrease chemotactic
transmigration in vivo, nor do they decrease transmigration triggered by thrombin. In
addition, there is often a significant residual transmigration (~10-30%) after PECAM-1
inhibition which suggests that other mechanisms may operate in passage through the
junction in cytokine-activated transmigration. These observations suggest that the
mechanisms operating in cytokine-activated and chemotactic transmigration overlap to
only a small degree. Neutrophils and monocytes from CD11a knock out mice do not
require PECAM-1 for transmigration, suggesting that CD11a and PECAM-1 somehow
operate in a similar pathway of migration. However, PECAM-1 knockout mice show no
clear evidence of a transmigration defect.
The involvement of VLA-4 in transmigration in vitro is variable. It is likely this reflects
redundancy with 2-integrins, as well as the degree of VCAM-1 expression on
endothelium, which in turn reflects the state of endothelial activation. It appears
unimportant in neutrophil transmigration in vitro, and in transmigration of activated T-
cells. Resting T-cell and NK cell cytokine-activated transmigration are reduced by 40%
and 30% respectively (Oppenheimer Marks et al 1991; Bianchi et al 1993). As firm
adhesion is reduced to a similar extent it is unclear whether this is a specific effect on
passage across the endothelium.
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Ectoenzymes in the control of leukocyte traffic
Ectoenzymes are membrane proteins that have their active site outside the cell. They
include proteases, nucleotidases, and oxidases, which can regulate leukocyte
transmigration.
Nucleotidases:
ATP is proinfammatory: ATP binds purinergic receptors of the P2X and P2Y
families, and induces proliferation by inducing cytokine expression, and activating
dendritic cells.
Adenosine is anti-infammatory: Adenosine inhibits neutrophil adhesion to the
microvascular endothelium by activating the adenosine receptors A 2A R abd A 2B R on
neutrophils. Adenosine prevents leukocyte activation- it inhibits L-selectin shedding and
expression of CD18 integrins by leukocytes, and down-regulates VCAM-1 and cytokine
expression by endothelial cells.
CD73