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

Xavier Aldeguer, Fotini Debonera, Abraham Shaked, Alyssa M. Krasinkas, Andrew E. Gelman, Xingyi Que, Gideon A. Zamir, Shungo Hiroyasu, Kellen K. Kovalovich, Rebecca Taub, Kim M. Olthoff

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

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 107 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.

Original languageEnglish
Pages (from-to)40-48
Number of pages9
JournalHepatology
Volume35
Issue number1
DOIs
StatePublished - 2002

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