Research Center, Maisonneuve-Rosemont Hospital, Department of Medicine, University of
Montréal, Montréal, Québec,
Canada H1T 2M4
C-Reactive protein (CRP), the classic acute-phase reactant
in humans, diminishes accumulation of neutrophils at inflammatory sites. To
evaluate the underlying mechanisms,
we have studied whether CRP and peptides derived from
CRP could affect the first step of neutrophil extravasation,
the L-selectin-mediated interaction of neutrophils with endothelial cells. CRP
markedly attenuated attachment of human neutrophils to cultured LPS-activated
human coronary
artery and pulmonary microvascular endothelial cells with
apparent IC50 values of 20 and 22 µg/ml, respectively.
At similar concentrations, CRP rapidly downregulated the expression
of L-selectin on the neutrophil surface, whereas it
failed to affect expression of CD11b and CD45 or to induce
granule enzyme release. The loss of L-selectin was due to cleavage and
shedding of the molecule from the cell surface, as
quantitated by the soluble form of L-selectin in cell-free supernatants. The effects
of CRP could be prevented by an anti-CRP antiserum and by KD-IX-73-4,
which inhibits shedding
of L-selectin. Inhibition of adhesion with CRP was additive
with function-blocking anti-E-selectin and anti-CD18 antibodies, but was not
additive with anti-L-selectin antibody.
Neutrophil attachment and L-selectin expression were also
diminished by CRP peptides 174-185 and 201-206, but not
peptide 77-82, albeit these peptides showed a weaker inhibitory effect
than the parent protein. These studies indicate a
specific activation-independent action of CRP and CRP peptides 174-185 and
201-206 on expression of L-selectin, and
suggest that by attenuating neutrophil adhesion to the endothelium and
consequently neutrophil traffic into tissues, native CRP and peptides 174-185 and
201-206 may be
major mechanisms to attenuate or limit the inflammatory
response. (J. Clin. Invest. 1997. 100:522-529.)