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Departments of
* Pathology and
Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
Veterans Administration Medical Center, Ann Arbor, MI 48105; and
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
The complement-derived anaphylatoxin, C5a, is a potent phlogistic
molecule that mediates its effects by binding to C5a receptor (C5aR;
CD88). We now demonstrate specific binding of radiolabeled recombinant
mouse C5a to mouse dermal microvascular endothelial cells (MDMEC) with
a Kd50 of 3.6 nM and to
15,000–20,000 receptors/cell. Recombinant mC5a competed effectively
with binding of [125I]rmC5a to MDMEC. Enhanced binding of
C5a occurred, as well as increased mRNA for C5aR, after in vitro
exposure of MDMEC to LPS, IFN-
, or IL-6 in a time- and
dose-dependent manner. By confocal microscopy, C5aR could be detected
on surfaces of MDMEC using anti-C5aR Ab. In vitro expression of
macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant
protein-1 (MCP-1) by MDMEC was also measured. Exposure of MDMEC to C5a
or IL-6 did not result in changes in MIP-2 or MCP-1 production, but
initial exposure of MDMEC to IL-6, followed by exposure to C5a,
resulted in significantly enhanced production of MIP-2 and MCP-1 (but
not TNF-
and MIP-1). Although LPS or IFN- alone induced some
release of MCP-1 and MIP-2, pre-exposure of these monolayers to LPS or
IFN-, followed by addition of C5a, resulted in synergistic
production of MIP-2 and MCP-1. Following i.v. infusion of LPS into
mice, up-regulation of C5aR occurred in the capillary endothelium of
mouse lung, as determined by immunostaining. These results support the
hypothesis that C5aR expression on MDMEC and on the microvascular
endothelium of lung can be up-regulated, suggesting that C5a in the
co-presence of additional agonists may mediate pro-inflammatory effects
of endothelial cells.
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