Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration.
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.
Aldeguer
Xavier
X
Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
Debonera
Fotini
F
Shaked
Abraham
A
Krasinkas
Alyssa M
AM
Gelman
Andrew E
AE
Que
Xingyi
X
Zamir
Gideon A
GA
Hiroyasu
Shungo
S
Kovalovich
Kellen K
KK
Taub
Rebecca
R
Olthoff
Kim M
KM
D000818:Animals; D001853:Bone Marrow / Q000737:chemistry*; D001854:Bone Marrow Cells / Q000737:chemistry* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006085:Graft Survival; D006498:Hepatectomy; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007728:Kupffer Cells / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004247:DNA