A
cyclic peptide,
Phe-[Orn-Pro-D-Cyclohexylalanine-Trp-Arg] (
F-[OPdChaWR]), was recently shown in vitro to antagonise the binding of C5a to its receptor (CD88) on human polymorphonuclear leukocytes (PMNs) and in vivo to inhibit the
neutropenia associated with
septic shock induced by
lipopolysaccharide (LPS) in rats. The aim of this study was to investigate whether
F-[OPdChaWR] inhibits C5a-mediated chemotaxis of human PMNs using a modified Boyden chamber and C5a-stimulated release of
cytokines from human monocytes in vitro. Approximately 50% of the chemotactic activity induced by 10 nM C5a was inhibited by 76 nM
F-[OPdChaWR]. This correlated with inhibition of C5a-induced polarisation of PMNs by
F-[OPdChaWR]. C5a alone failed to induce release of the inflammatory
cytokines interleukin(IL)-1beta, tumour
necrosis factor (
TNF)-alpha, and
IL-6 from human monocytes at concentrations up to 100 nM. However, in the presence of low concentrations of LPS (50 ng/mL), both IL-1beta and
TNF-alpha were stimulated by 1 nM C5a. This co-stimulation was inhibited by
F-[OPdChaWR] with IC(50)s of 0.8 and 6.9 nM for release of
TNF-alpha and IL-1beta, respectively. No agonist activity was detected for
F-[OPdChaWR] in either the chemotaxis or
cytokine release assays at concentrations up to 50 microM. These results show that
F-[OPdChaWR] inhibits several important inflammatory activities of C5a and suggest that
C5a receptor antagonists may be effective in the treatment of inflammatory diseases mediated by C5a.