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2-Macroglobulin Gene Expression in Hepatocytes Via IL-6 Release from Kupffer Cells1
*
Institut für Biochemie und Molekulare Zellbiologie and
Abteilung für Immunologie, Georg-August-Universität Göttingen, Göttingen, Germany
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 
2-macroglobulin
(2MG) 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- or IL-1
, enhanced 2MG 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 2MG mRNA
in HC. However, medium of KC stimulated with rrC5a plus LPS induced
2MG 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
2MG 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.
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