Anaphylatoxin C5a Actions in Rat Liver: Synergistic Enhancement by C5a of Lipopolysaccharide-Dependent α2-Macroglobulin Gene Expression in Hepatocytes Via IL-6 Release from Kupffer Cells

Abstract

The effects of the anaphylatoxins C5a and C3a on the liver are only poorly characterized in contrast to their well known systemic actions. Recently, it has been demonstrated that the anaphylatoxin C5a enhanced glucose output from hepatocytes (HC) indirectly via prostanoid release from Kupffer cells (KC). In the present study, it is shown that recombinant rat C5a (rrC5a), together with LPS, activated the gene of the acute phase protein α2-macroglobulin (α2MG) in HC also indirectly via IL-6 release from KC. RrC5a alone increased neither IL-6 mRNA in nor IL-6 release from KC, whereas LPS alone did so. However, rrC5a synergistically enhanced the LPS-dependent increase in IL-6 mRNA and IL-6 release. Only rIL-6, but not TNF-α or IL-1β, enhanced α2MG mRNA in HC. In line with the actions of rrC5a and LPS on KC, conditioned medium of KC stimulated only with rrC5a did not increase α2MG mRNA in HC. However, medium of KC stimulated with rrC5a plus LPS induced α2MG mRNA expression in HC more strongly than medium from cells stimulated only with LPS; thus, C5a acted synergistically with LPS. 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 α2MG gene expression. 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. This provides evidence for another important function of C5a in the regulation of hepatocellular defense reactions.

Differences in the Involvement of Prostanoids from Kupffer Cells in the Mediation of Anaphylatoxin C5a-, Zymosan-, and Lipopolysaccharide-Dependent Hepatic Glucose Output and Flow Reduction

“…These substances elicited effector functions of hepatocytes only indirectly by means of intercellular communication (Hespeling et al, 1995;Mäck et al, 2001;Püschel et al, 1996;Schieferdecker et al, 1999). In agreement with these observations, putative receptors for C5a and zymosan were predominantly or even exclusively expressed by KCs but not or only scarcely by hepatocytes (Fig.…”

“…5). However, this faint mRNA expression in hepatocytes obviously did not lead to the expression of functional C5L2 protein, because under normal conditions hepatocytes did not respond to C5a (Hespeling et al, 1995;Mäck et al, 2001;Schlaf et al, 1999) nor to C5adesarg (unpublished observations).…”

Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats

“…A by-product of complement activation, the complement factor 5a (C5a), is a potent pro-inflammatory mediator during I/R injury in various organs [9 -13]. Activation of C5a receptors on PMNs leads to chemotaxis, expression of cellular adhesion receptors, release of pro-inflammatory mediators [14 -16] and release of pro-inflammatory cytokines from Kupffer cells [17]. Experimental studies have shown that blockade of complement activation results in improved microcirculation [8] and reduced leukocyte adherence [18] following hepatic I/R.…”

Expression of a Functional C5a Receptor in Regenerating Hepatocytes and Its Involvement in a Proliferative Signaling Pathway in Rat

“…Contrasting with a lack of C5aR expression on normal rat hepatocytes, C5aR expression has been observed at both mRNA and protein levels under inflammatory conditions, i.e., in IL-6-challenged rats (9). Likewise, recombinant rat C5a, together with LPS, activates the ␣ 2 -macroglobulin gene (coding for an APP) in rat hepatocytes (10). Recently, complement has been considered as a regulator of cell proliferation and differentiation during development (11,12), and in this context, has been suggested to play novel roles as a regulator of noninflammatory processes.…”