Complement C3a, complement C5a and C567 are both chemotactic factors. C5a is also a potent activator of neutrophils, basophils and macrophages and causes induction of adhesion molecules on vascular endothelial cells.
The high molecular weight chemotactic factor, C567, derived from the fifth, sixth, and seventh components of complement, induces chemotaxis in rabbit polymorphonuclear leukocytes by activating a serine esterase. This esterase is capable of splitting acetyl DL-phenylalanine/3-naphthyl ester; it exists in or on the polymorphonuclear leukocyte in an inert form termed proesterase 1; the active form is known as esterase 1.
C567 incubated with the rabbit polymorphonuclear leukocyte changes the cell in such a manner that it no longer is capable of giving a chemotactic response; this specific decrease in chemotactic responsiveness is called "deactivation".
The activation of proesterase 1 is involved in the deactivation by C567. If a cell is deactivated by C567 it will not respond chemotactically to the other complement-derived chemotactic factors (C3a, C5a) nor to bacterial chemotactic factors; that is, it is deactivated to all of them. Similarly, if a cell is deactivated by C3a or C5a, it is also deactivated to all the others including the bacterial factors. However, incubation of rabbit polymorphonuclear leukocytes with bacterial factor does not induce deactivation to either the bacterial factor not to any of the complement-derived factors.
Complement activation from classical, alternative, and lectin pathways leads to production of the anaphylatoxins C3a and C5a, which are small (Mr of ∼8,700-11,000) polypeptides released from their precursor proteins C3 and C5, respectively, by C3/5 convertases. Both C3a and C5a are well known as chemotactic, oxidant-inducing, and degranulating agents for myeloid cells.
The C3a receptor (C3aR) and the C5a receptor (C5a; CD88) are both GPCRs, which couple usually to Gi and share ∼40% sequence identity. There is a third anaphylatoxin receptor, C5L2, which binds C5a, but according to most reports its activation does not cause any cell stimulation, suggesting that this may be a scavenger receptor for C5a.
Receptors for C3a and C5a are widely expressed and are not only found on cell types of myeloid lineage, but also on T lymphocytes, smooth muscle cells, neurons, and glial, endothelial, and epithelial cells.
While C5a functions as a potent chemotactic factor for most leukocytes both in vitro and in vivo, C3a is only a moderately effective chemoattractant for various leukocytes in vitro. Even cell types that showed a modest chemotactic response to C3a in vitro (i.e., eosinophils) failed to be chemoattracted by C3a in vivo. This may be explained in part by the presence of serum carboxypeptidase N, which inactivates C3a by cleaving the carboxyl-terminal arginine residue. Although carboxypeptidase N also converts C5a to C5a(desArg), this modified polypeptide still retains a reduced functional ability and affinity for the C5aR, whereas C3a(desArg) loses the complete ability to bind and activate the Ca3R.
1. Becker E L. (1972). The relationship of the chemotactic behavior of the complement-derived factors, C3a, C5a, and C567, and a bacterial chemotactic factor to their ability to activate the proesterase 1 of rabbit polymorphonuclear leukocytes. The Journal of experimental medicine, 135(2), 376-387.
2. Schraufstatter I U, et al. (2009). C3a and C5a are chemotactic factors for human mesenchymal stem cells, which cause prolonged ERK1/2 phosphorylation. The Journal of Immunology, 182(6), 3827-3836.