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

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 10 7 donor bone marrow cells capable of expressing IL-6 (IL-6 ؉/؉ ). Conversely, IL-6 ؉/؉ recipients received IL-6 ؊/؊ marrow.

IL-6 deficiency in mice neither impairs induction of metabolic genes in the liver nor affects blood glucose levels during fasting and moderately intense exercise

“…Therefore if IL-6-deficient mice were forced to run till exhaustion, it is possible that lack of IL-6 would result in impaired adaptation of hepatic glucose metabolism to intense and prolonged exercise. However, more rigorous exercise conditions could also lead to hepatic tissue damage and infiltration of inflammatory cells [32], which could stimulate IL-6 production in intrahepatic cells and induce IL-6-mediated tissue repair mechanisms [33]. Il6 −/− mice have defective liver repair mechanisms and blunted induction of genes involved in cell cycle progression, liver growth and maintenance of metabolic homeostasis, including gluconeogenetic enzyme genes and Igfbp1 after partial hepatectomy [11,34,35].…”

Clinical Implications of Advances in the Basic Science of Liver Repair and Regeneration

“…These include portal blood flow, insulin and glucagon production by the pancreas, the ratio of a soluble factor to the size of the liver remnant, glucose metabolism and plasma amino acid composition (12)(13)(14)(15)(16) (19,20). IL-6, produced by Kupffer cells, is similarly necessary for normal liver regeneration (21). It may act as a direct hepatocyte mitogen and also help to manage the acute-phase response of hepatocytes (22)(23)(24).…”

Contribution of Toll‐like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration†

“…It is well established that tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), produced by nonparenchymal liver cells, play a critical role in activation of the priming phase. 7,8,13,14 Indeed, Tnfr type I Ϫ/Ϫ or Il-6 Ϫ/Ϫ mice exhibit impairment of liver regeneration after PH. 7,8 Moreover, normal activation of nuclear factor B (NF-B) and signal transduction and activation of transcription (STAT) 3, which yield signaling factors TNF-␣ and IL-6, respectively, are also essential for liver regeneration.…”