Induction of Functional Anaphylatoxin C5a Receptors on Hepatocytes by In Vivo Treatment of Rats with IL-6

Abstract

In normal rat liver, anaphylatoxin C5a receptors (C5aR) are only expressed by nonparenchymal cells, mainly Kupffer cells and hepatic stellate cells, but not by parenchymal cells, i.e., hepatocytes (HC). Nevertheless, C5a stimulates glucose output by HC. This HC-specific defense reaction is induced indirectly via prostanoids secreted by the C5aR-expressing Kupffer cells and hepatic stellate cells. It is shown here that under inflammatory conditions simulated by in vivo treatment of rats with IL-6 C5aR mRNA and protein were induced in HC in a time-dependent manner. Maximal mRNA and protein expression were observed at 4–8 h and 8–10 h, respectively, after IL-6 injection. The newly expressed receptors were functional, because recombinant rat C5a significantly activated glycogen phosphorylase in HC isolated from IL-6-treated but not in HC from control rats. In perfused livers of IL-6-treated animals in contrast to control animals, recombinant rat C5a-induced glucose output was not impaired by inhibition of prostanoid synthesis and function with the cyclooxygenase inhibitor indomethacin and the thromboxane receptor antagonist daltroban. These results indicate that HC-specific defense reactions might be differently regulated under normal and inflammatory conditions as shown here for the indirect prostanoid-dependent or direct C5a-induced activation of hepatocellular glycogen phyosphorylase and glucose output in control or IL-6-treated rats, respectively.

Enhancement of Human Cancer Cell Motility and Invasiveness by Anaphylatoxin C5a via Aberrantly Expressed C5a Receptor (CD88)

“…CXCR4 expression is also activated by mutations in genes that alter levels of hypoxiainducible factors, and gene fusion events. Interleukin (IL)-6-induced C5aR expression in rat hepatocytes (37) suggests that C5aR can be expressed in response to specific cytokines that are rich in the cancer microenvironment (20,38). However, IL-6 and IFN-g did not induce C5aR expression in HuCCT1 cells (unpublished data).…”

Role of cytokines in photodynamic therapy-induced local and systemic inflammation

“…IL-6 is characterised as a proinflammatory cytokine primarily because of its role in release of acute-phase proteins (Baumann and Gauldie, 1994;Suffredini et al, 1999) and complement activation (Knittel et al, 1997;Minta et al, 2000;Schieferdecker et al, 2000). In some reports, IL-6 has also been implicated in neutrophil migration (Dalrymple et al, 1995;Romano et al, 1997;Hurst et al, 2001;Suwa et al, 2001) and has been shown to contribute to the rise in circulating neutrophils observed following Photofrin-PDT .…”

Constitutive Expression and Regulation of Rat Complement Factor H in Primary Cultures of Hepatocytes, Kupffer Cells, and Two Hepatoma Cell Lines

“…Therefore conclusions drawn from results obtained with hepatoma cells should not be extended to wild-type cells without further analyses. For instance, HepG2 cells, FAO, and H4IIE cells express the C5a receptor (CD88) constitutively, but primary HC do not unless they are stimulated with proinflammatory cytokines such as IL-6 or IL-1␤ (Schieferdecker et al, 1997(Schieferdecker et al, , 2000Schlaf et al, 1999).…”