Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells

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. In contrast to its well-defined systemic functions, the actions of anap...

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Bibliographic Details
Published in:International Immunopharmacology 2001-03, Vol.1 (3), p.469-481
Main Authors: Schieferdecker, Henrike L, Schlaf, Gerald, Jungermann, Kurt, Götze, Otto
Format: Article
Language:English
Subjects:
Acute-Phase Proteins - biosynthesis
Animals
Antigens, CD - physiology
Biological and medical sciences
C5a receptor expression
Cell–cell communication
Complement
Complement C5a - physiology
complement component C5
complement component C5a
Cytokines - biosynthesis
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Glucose - secretion
Hepatic defense reactions
Hepatitis - immunology
Hepatocytes - immunology
Humans
In Vitro Techniques
Inflammation
Inflammation Mediators - metabolism
Kupffer Cells - immunology
Liver - cytology
Liver - immunology
Molecular immunology
Prostaglandins - secretion
Rats
Receptor, Anaphylatoxin C5a
Receptors, Complement - physiology
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Summary: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. In contrast to its well-defined systemic functions, the actions of anaphylatoxins in these organs are poorly characterized. 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). In the normal rat liver, the C5aR is only expressed by nonparenchymal cells, i.e. strongly by Kupffer cells (KC) and hepatic stellate cells (HSC) and weakly by sinusoidal endothelial cells (SEC), but not expressed by the parenchymal hepatocytes (HC). Accordingly, direct effects of C5a were only found in the C5aR-expressing KC and HSC: C5a induced the release of prostanoids from KC and HSC and enhanced the LPS-dependent release of interleukin-6 from KC. These soluble mediators indirectly influenced effector functions of the C5aR-free HC. C5a enhanced the glycogen phosphorylase activity and thus the glucose output from HC indirectly via prostanoids released from KC and HSC. Glucose can serve as an energy substrate as well as an electron donor for the synthesis of reactive oxygen intermediates by KC. Moreover, C5a also enhanced transcription of the gene for the type-2 acute phase protein α 2-macroglobulin in HC indirectly by increasing LPS-dependent IL-6 release from KC. Under pathological conditions, C5aR was found to be upregulated in various organs including the liver. Simulation of inflammatory conditions by treatment of rats with IL-6, a main inflammatory mediator in the liver, caused a de novo expression of functional C5aR in HC. In livers of IL-6-treated rats, C5a initiated glucose output from HC and perhaps other HC-specific defense reactions directly without the intervention of soluble mediators from nonparenchymal cells.
ISSN:1567-5769
1878-1705
DOI:10.1016/S1567-5769(00)00038-2