N-formylpeptide and complement C5a receptors are expressed in liver cells and mediate hepatic acute phase gene regulation.

Abstract

SummaryAlthough the classical chemotactic receptor for complement anaphylatoxin C5a has been associated with polymorphonuclear and mononuclear phagocytes, several recent studies have indicated that this receptor is expressed on nonmyeloid cells including human endothelial cells, vascular smooth muscle cells, bronchial and alveolar epithelial cells, hepatocytes, and in the human hepatoma cell line HepG2. In this study, we examined the possibility that other members of the chemotactic receptor family are expressed in HepG2 cells and human liver, and the possibility that such receptors mediate changes in acute phase gene expression in HepG2 cells. Using polymerase chain reaction (PCR) amplification of HepG2 mRNA with primers based on highly conserved regions of the chemotactic subgroup of the G protein-coupled receptor family, we identified a PCR fragment from the formyl-methionyl-leucyl-phenylalanine (FMLP) receptor, as well as one from the C5a receptor. Immunostaining with antipeptide antisera to FMLPR confirmed the presence of this receptor in HepG2 cells. Receptor binding studies showed specific saturable binding of a radioiodinated FMLP analogue to HepG2 cells (Ka • 2.47 nM; R ~ 6 x 103 plasma membrane receptors per cell). In situ hybridization analysis showed the presence of FMLPIk mRNA in parenchymal cells of the human liver in vivo. Both C5a and FMLP mediated concentrationand time-dependent changes in synthesis of acute phase proteins in HepG2 cells induding increases in complement C3, factor B, and otl-antichymotrypsin, as well as concomitant decreases in albumin and transferrin synthesis. The effects of CSa and FMLP on the synthesis of these acute phase proteins was evident at concentrations as low as 1 nM, and they were specifically blocked by antipeptide antisera for the corresponding receptor. In contrast to the effect of other mediators of hepatic acute phase gene regulation, such as interleukin 6, the effects of C5a and FMLP were reversed by increased concentrations well above the saturation point of the respective receptor. These results suggest that acute phase gene regulation by CSa and FMLP is desensitized at high concentrations, a property that is unique among the several known mechanisms for hepatic acute phase gene regulation.

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

“…Functional expression of FPR1 has also been shown for human bone marrow mesenchymal stem cells, suggesting a potential role for migration and engraftment of such cells into injured tissues (9,10) or for osteoblast differentiation (11). Moreover, FPR1 has been described to be involved in the regulation of acute-phase protein production by A549 lung cells (12) and human HepG2 hepatoma cells (13). Furthermore, FPR1 has been detected in several kinds of epithelial cells, e.g.…”

The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells

“…Recently, a number of host-derived chemotactic agonists of FPR have been identified, including formylpeptides potentially released by mitochondria of ruptured cells (Rabiet et al, 2005), annexin I produced by activated epithelia (Xia et al, 2002) and a neutrophil granule protein, cathepsin G (Sun et al, 2004). In addition, functional FPR has been detected in cells of nonhaematopoietic origin, such as lung epithelial cells (Rescher et al, 2002) and hepatocytes (McCoy et al, 1995). These findings expanded the spectrum of pathophysiologic processes in which FPR may have a function.…”

A New Staphylococcal Anti-Inflammatory Protein That Antagonizes the Formyl Peptide Receptor-Like 1

“…The role of C5a and fMLP in host defense is clear, because they have been implicated not only in leukocyte recruitment but also on the hepatic synthesis of acute phase proteins (8), as well as activation of NF-B and production of inflammatory cytokines by phagocytes (37). Furthermore, targeted gene disruption of FPR in mice impaired the antibacterial response (38).…”

“…FPR is the high-affinity receptor for fMLP that is activated by picomolar to nanomolar concentrations of fMLP and is expressed on phagocytes but also on cell types as diverse as hepatocytes, dendritic cells, astrocytes, and microglia cells (7)(8)(9). Two other homologs of the FPR have been identified, FPR-like 1 (FPRL1) and FPR-like 2 (FPRL2).…”