C5a receptor has been identified as a leukocyte chemotactic receptor to two intrinsic chemical mediators, C5a and the S19 ribosomal protein dimer, so far. We found an Escherichia coli protein that also induced the chemotactic responses of monocytes and polymorphonuclear leukocytes via the C5a receptor. We identified the E. coli-derived chemoattractant to be Skp by the molecular size and the N-terminal amino acid sequence. Skp is a periplasmic chaperone protein widely present in gram-negative bacterial species. Immunoabsorption experiments indicated that Skp was the major leukocyte chemotactic factor in the E. coli extract. Receptor-antagonizing experiments with analogue peptides of S19 ribosomal protein and C5a receptor is one of the most important leukocyte receptors involving in the inflammatory reaction. C5a receptor was initially identified as the receptor of C5a, which is a 74 amino acid peptide liberated from the ␣-chain of complement C5 by C5 convertases during the complement activation. C5a attracts polymorphonuclear leukocytes (PMNs), monocytes, and many other leukocytes via the C5a receptor. In addition to this, C5a stimulates PMNs via the C5a receptor to release granule contents and to produce radical oxygen species.1 C5a also promotes monocytes/macrophages via the C5a receptor to synthesize interleukin (IL)-1, IL-6, and several other cytokines.2 The C5a receptor gene, which is located on chromosome 19 q13.3-13.4 (from the Genome Database), is also expressed in nonmyeloid cells such as astrocytes and hepatocytes at least under inflamed conditions. Hepatocyte C5a receptor would participate in the acute phase protein synthesis. Besides, we have realized that the S19 ribosomal protein (RP S19) dimer attracts monocytes via the C5a receptor as in the case of C5a.3 RP S19 is a component of the small subunit of ribosome, being composed of 145 amino acid residues. RP S19 is intermolecularly crosslinked by a transglutaminase-catalyzed reaction 4,5 during apoptotic process and the dimer is liberated from the apoptotic cells. 6,7 The RP S19 dimer attracts monocytes/ macrophages and promotes them to phagocytically clear the apoptotic cells from which the chemoattractant molecule has been originated. In contrast to this, the RP S19 dimer antagonizes the C5a receptor-mediated chemotaxis of PMNs.
3Whereas a calculated homology in the amino acid sequence between C5a and RP S19 is only 4%, C5a and the RP S19 dimer activate monocyte C5a receptor by the same interaction mechanism. The C5a receptor, composed of 350 amino acid residues, is a member of the G-protein-coupled 7 transmembrane protein receptor family. The ligand-receptor interaction between C5a or the RP S19 dimer and C5a receptor is a two-step binding process. 8 In the first binding, a basic cluster of the ligand molecules; a cluster three-dimensionally formed by His15, Arg46, and Lys49 of C5a, or a cluster with the Lys41-His42-Lys43 tandem of RP S19, seems to bind to the amino-terminal acidic moiety of C5a receptor, which is composed of several Asp residues ...