1: Hepatology. 2002 Jan;35(1):40-8. 

Interleukin-6 from intrahepatic cells of bone marrow origin is required for
normal murine liver regeneration.

Aldeguer X, Debonera F, Shaked A, Krasinkas AM, Gelman AE, Que X, Zamir GA,
Hiroyasu S, Kovalovich KK, Taub R, Olthoff KM.

Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.

Interleukin-6 (IL-6) is required for normal liver regeneration, but the specific
cellular source of this growth factor is unknown. We investigated whether this
signal originates from the resident macrophage, the Kupffer cell. Using a murine
model of bone marrow transplantation, we replaced recipient bone marrow-derived
cells, including Kupffer cells, with cells of donor genetic phenotype.
Recipients deficient in IL-6 (IL-6(-/-)) were lethally irradiated, then rescued
with 10(7) donor bone marrow cells capable of expressing IL-6 (IL-6(+/+)).
Conversely, IL-6(+/+) recipients received IL-6(-/-) marrow. Successful
engraftment was measured by the presence of the Y chromosome SRY locus in the
livers of female recipients receiving male marrow, in situ IL-6 expression by
Kupffer cells, and up-regulation of IL-6 in splenocytes after activation with
lipopolysaccharide (LPS). Kupffer cell isolation in IL-6(-/-) females receiving
IL-6(+/+) male marrow clearly showed the presence of the SRY locus and IL-6
disrupted allele, whereas males receiving female marrow demonstrated no SRY or
IL-6 signals, confirming the extent of replacement. Replacement of these cells
in IL-6(-/-) mice with IL-6(+/+) bone marrow successfully restored the
regenerative response after partial hepatectomy (PHx) as indicated by signal
transduction and activator of transcription 3 (STAT3) activation and hepatocyte
DNA replication. Alternatively, complete replacement of Kupffer cells in
IL-6(+/+) mice by transplantation with IL-6(-/-) cells significantly inhibited
liver regeneration and was partially restored by administration of IL-6. This
investigation demonstrates a paracrine mechanism by which cells of bone marrow
origin, most likely Kupffer cells, regulate the regenerative capacity of the
hepatocyte through IL-6 expression.

PMID: 11786958 [PubMed - indexed for MEDLINE]


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