Disease relevance of C5

• Thus, C5a alone appears to have only a limited role in the induction of liver fibrosis [1].
• These results suggest that C5a, besides enhancing glucose output via prostanoids, is involved in the initiation of the acute phase response in HC via proinflammatory cytokines from KC [2].
• Since the intrathecal generation of anaphylatoxin C5a has been shown to mediate inflammatory effects within the central nervous system, we sought to characterize the cellular expression of the mRNA for the C5a receptor (C5aR, CD88) in brains of rats with experimental diffuse axonal injury (DAI) by in situ hybridization [3].
• The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease [4].
• C5a antagonists could therefore have broader therapeutic benefits than nonsteroidal antiinflammatory drugs as antiarthritic agents for rheumatoid arthritis [5].

Psychiatry related information on C5

• Clinical studies over the past several years have correlated the use of anti-inflammatory drugs with a decrease in the incidence and progression of AD dementia and/or dysfunction, supporting a role for gliosis and inflammation in AD pathogenesis (reviewed in ref. 6). C5a, a product of C' activation, is chemotactic for microglia [6].

High impact information on C5

• These data indicate that sepsis causes an excessive production of C5a, which compromises the bactericidal function of neutrophils [7].
• Blood neutrophils from these rats contained on their surfaces the powerful complement activation product C5a [7].
• Protective effects of C5a blockade in sepsis [7].
• In contrast, when companion CLP rats were treated with IgG antibody against C5a, survival rates were significantly improved, levels of bacteremia were considerably reduced, and the H2O2 response of blood neutrophils was preserved [7].
• Bacterial colony-forming units in spleen and liver were very high in CLP rats treated with preimmune IgG and very low in CLP rats treated with IgG antibody against C5a, similar to values obtained in rats that underwent 'sham' operations (without CLP) [7].

Chemical compound and disease context of C5

• Inhibition of C5 or absence of C6 protects from sepsis mortality [8].
• Thus, the hyperalgesia produced by fMLP and C5a is similar to that produced by leukotriene B4 in that it is dependent on PMNLs and independent of the cyclo-oxygenation of arachidonic acid [9].
• In this study, we addressed the contribution of PMNLs to hyperalgesia evoked by the peptide chemotactic factors N-formyl-methionyl-leucyl-phenylalanine (fMLP) and the anaphylatoxin fragment of the fifth component of the complement pathway (C5a) [9].
• The nonsteroidal anti-inflammatory indomethacin did not attenuate C5a and fMLP-induced hyperalgesia [9].
• These studies suggest the following pathogenesis of burn edema: thermal trauma causes complement activation with anaphylatoxin release and mast cell secretion of histamine, leading to enhancement of xanthine oxidase activity and increased production of oxygen radicals which damage endothelial cells [10].

Biological context of C5

• Anaphylatoxins (C5a and C3a), which are generated during complement activation, have recently been shown to increase glucose output from hepatocytes (HC) in perfused rat liver [11].
• The stimulatory effects of KC-conditioned medium could partially be inhibited by a neutralizing anti-IL-6 Ab, indicating that KC-derived IL-6 was a major mediator in C5a- plus LPS-elicited alpha(2)MG gene expression [2].
• Nucleotide and corrected amino acid sequence of the functional recombinant rat anaphylatoxin C5a [12].
• Characterization of C3a and C5a receptors in rat cerebellar granule neurons during maturation. Neuroprotective effect of C5a against apoptotic cell death [13].
• Consistent with this desensitization of Ca2+ mobilization, inositol 1,4,5-trisphosphate release in RBL-2H3 cells expressing both ET-C5aR and ET-FR revealed that fMLP and C5a cross-desensitized each other's ability to stimulate phosphoinositide hydrolysis [14].

Anatomical context of C5

• Correspondingly, it was found that hepatocytes, in contrast to Kupffer cells, did not express C5a receptors [15].
• At this time-point, C5a directly activated glycogen phosphorylase in isolated hepatocytes and enhanced glucose output in perfused livers without the involvement of prostanoids [15].
• Anaphylatoxin C5a receptor mRNA is strongly expressed in Kupffer and stellate cells and weakly in sinusoidal endothelial cells but not in hepatocytes of normal rat liver [11].
• The liver can be a primary target organ for the C5a anaphylatoxin since the liver is directly connected to the gut, via the mesenteric veins and portal vein which is a main source of complement activating lipopolysaccharides (LPS) [16].
• Growing evidence obtained in recent years indicates that anaphylatoxin C5a receptors (C5aR) are not restricted to myeloid cells but are also expressed on nonmyeloid cells in different tissues such as brain, lung, skin and liver [16].

Associations of C5 with chemical compounds

• Induction of anaphylatoxin C5a receptors in rat hepatocytes by lipopolysaccharide in vivo: mediation by interleukin-6 from Kupffer cells [15].
• The effects of the anaphylatoxins C5a and C3a on the liver are only poorly characterized in contrast to their well known systemic actions [2].
• The anaphylatoxin C5a is a pro-inflammatory factor generated from C5 during complement activation [17].
• Proteolytic removal of the C-terminal arginine of C5a (C5adesArg) reduced spasmogenic potency of rat C5a by only 4-fold compared to a 3,000-fold reduction for human C5adesArg [17].
• Recombinant rat C5a with a 6 histidine tag at the N-terminus was expressed in bacteria, purified and renatured [12].

Physical interactions of C5

• However, little is known about the role of the C5a/C5aR complex in liver and its involvement during a proliferative process [18].

Regulatory relationships of C5

• CONCLUSIONS: Thus, IL-6 from Kupffer cells appears to be the main mediator of LPS-induced de novo expression of C5a receptors in hepatocytes [15].
• Activation of the complement system generates the anaphylatoxin C5a whose activities are mediated through its binding to the widely expressed C5aR [18].
• Monocyte-macrophages from animals treated with IFN-gamma exhibited defective chemotactic responses when tested in vitro and furthermore, monocytes cultured with IFN-gamma (25 to 500 U/ml) in vitro had significantly suppressed chemotactic responses to the complement fragment C5a (p less than 0.005) [19].

Other interactions of C5

• In order to corroborate this mechanism, the distribution of anaphylatoxin receptors in the different cell types of rat liver was determined by quantitative RT-PCR with primers specific for the rat C5a receptor (rC5aR) using RNA isolated from KC, sinusoidal endothelial cells (SEC), hepatic stellate cells (HSC) and HC [11].
• In cocultures of hepatocytes with Kupffer cells, LPS induced C5a receptors in hepatocytes in an IL-6-dependent manner [15].
• In addition, C5a did not upregulate specific mRNA for the profibrotic cytokine TGF-beta1 in either isolated KC or HSC [1].
• The effect of a stimulation by a C5a agonist upon the synthesis of a growth factor/receptor pair (hepatocyte growth factor/c-Met) was also evaluated [18].
• Our data demonstrated an up-regulated expression of hepatocyte growth factor and c-Met mRNAs, but we failed to observe a direct mitogenic effect of C5a in culture [18].

Analytical, diagnostic and therapeutic context of C5

• Immunohistochemistry demonstrated prominent phosphorylated (p) inhibitory factor-kappaB (IkappaB)-alpha staining of intestinal tissue after GI/R, whereas anti-C5 reduced p-IkappaB-alpha expression [20].
• However, a significantly increased expression of cyclin E and D1mRNA levels, as well as an increased BrdU incorporation, were observed in rats given an i.v. C5a agonist injection following an 80% partial hepatectomy [18].
• Insertion of residues LLH between Gln-3 and Lys-4 in a recombinant human C5a molecule using site-directed mutagenesis failed to enhance potency [17].
• Pep-A bound to PL37 and to C5a with very slow dissociation as determined by analysis using surface plasmon resonance, whereas Pep-B failed to bind at all [21].
• BACKGROUND: C5a has been implicated in numerous pathophysiological conditions, including ischemia/reperfusion (I/R) injury of the kidney [22].

References