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Interleukin‐6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration
Author(s) -
Aldeguer Xavier,
Debonera Fotini,
Shaked Abraham,
Krasinkas Alyssa M.,
Gelman Andrew E.,
Que Xingyi,
Zamir Gideon A.,
Hiroyasu Shungo,
Kovalovich Kellen K.,
Taub Rebecca,
Olthoff Kim M.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.30081
Subject(s) - bone marrow , liver regeneration , biology , paracrine signalling , kupffer cell , cytokine , hepatocyte , microbiology and biotechnology , cancer research , immunology , regeneration (biology) , in vitro , biochemistry , receptor
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.