Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration
Open accessAbstract
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.
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Kupffer cells are the major source of IL-6 in the early expression after PHx.
“Whereas Kupffer cells are the major source of IL-6 in this early expression (70)”
From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [70]
The Results describe IL-6 expression peaking 2–4 hours after partial hepatectomy, and the Discussion identifies Kupffer cells as the most likely principal local source, with little contribution from other nonparenchymal cells. The paper does not establish definitively that Kupffer cells are the major source; the claim drops that qualification. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTransplantation of wild type bone marrow into IL-6 deficient animals rescues normal liver function in response to targeted hepatic injury.
“Previously, it was demonstrated that transplantation of wild type bone marrow into IL-6 deficient animals is able to rescue normal liver function in response to targeted hepatic injury, proving the importance of immune cells in providing IL-6 to hepatocytes [8].”
From Synthesis of IL-6 by Hepatocytes Is a Normal Response to Common Hepatic Stimuli (2014) · cites this paper as [8]
The Abstract reports that wild-type bone marrow restored the regenerative response in IL-6-deficient mice after partial hepatectomy, measured by STAT3 activation and hepatocyte DNA replication. It also identifies bone-marrow-derived cells, most likely Kupffer cells, as a source of IL-6. The paper does not establish that transplantation restored normal liver function more broadly. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe accumulation of IL-6 after PHx is likely a result of increased IL-6 secretion by Kupffer cells to promote an efficient regenerative response.
“This is likely a result of an increased IL-6 secretion by Kupffer cells (Aldeguer et al., 2002) to promote an efficient regenerative response.”
From Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib (2017) · cites this paper as Aldeguer et al., 2002
Kupffer cells and bone marrow-derived macrophages and their mediators, such as TNF and IL-6, play key roles in liver regeneration.
“Kupffer cells and bone marrow-derived macrophages and their mediators, such as TNF and IL-6, play key roles in liver regeneration, as demonstrated by knockout, depletion, and bone marrow transplantation studies [64–70].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [65]
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References 33 · Cited by 138
Research works printed but not linked: 3
- Smedsrod B, Pertoft H. Preparation of pure hepatocytes and reticu- loendothelial cells in high yield from a single rat liver by means of HEPATOLOGY, Vol. 35, No. 1, 2002
- ALDEGUER ET AL. 47 15273350, 2002, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1053/jhep.2002.30081, Wiley Online Library on [18/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License percoll centrifugation and selective adherence. J Leukoc Biol 1985; 38:213-230.
- ALDEGUER ET AL. HEPATOLOGY, January 2002 15273350, 2002, 1, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1053/jhep.2002.30081, Wiley Online Library on [18/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
- Authors
- Aldeguer, X., Debonera, F., Shaked, A., Krasinkas, A. M., Gelman, A. E., Que, X., Zamir, G. A., Hiroyasu, S., Kovalovich, K. K., Taub, R., & Olthoff, K. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Olthoff, Kim M.
- ORCID
- Venue
- Hepatology
- Published
- 2002-01
- Volume
- 35
- Issue
- 1
- Pages
- 40-48
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2109133986
- Cited by
- 138
- References
- 33
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 8 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 2 · 2012: 10
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Health Center (P30 DK50306)
- Fred and Suzanne Biesecker Center for Pediatric Liver Disease at the Children' Hospital of Philadelphia
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- interleukin-6, liver regeneration, Kupffer cells, bone marrow transplantation, partial hepatectomy, STAT3 activation, paracrine signaling, IL-6-deficient mice, hepatocyte regeneration
- MeSH terms
- Animals, Bone Marrow, Bone Marrow Cells, DNA, DNA-Binding Proteins, Female, Graft Survival, Hepatectomy, Kupffer Cells, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Spleen, Signal Transduction, Trans-Activators, Interleukin-6, Bone Marrow Transplantation, Mice, Knockout, Models, Animal, STAT3 Transcription Factor, Mice
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