Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation
Abstract
Background & aims Interleukin-6 (IL-6) is a crucial factor in liver regeneration following partial hepatectomy (PH); however, the role of IL-6 and IL-6 trans-signaling in particular, in hepatocyte mitosis remains controversial. IL-6 trans-signaling relies upon the release of the soluble IL-6R (sIL-6R), which binds IL-6 to form an agonistic IL-6/sIL-6R complex. Herein we have examined the hypothesis that IL-6 trans-signaling plays a crucial and distinct role in liver regeneration following PH. Methods The specific IL-6/sIL-6R antagonist, sgp130Fc, was expressed in mice and analyzed for its effect on hepatocyte mitosis following PH. Alternatively, we examined the effect of the IL-6/sIL-6R super-agonist, Hyper-IL-6, or IL-6 expressed either alone or in combination with hepatocyte growth factor (HGF) on hepatocyte mitosis in the absence of PH. Results Following PH, the dramatic rise of circulating IL-6 levels is accompanied by a concurrent ∼2-fold increase in circulating sIL-6R levels. Ectopic expression of sgp130Fc reduced hepatocyte mitosis by about 40% at early times following PH, while substantially reducing AKT, but not STAT3, activation. But, ectopic Hyper-IL-6 expression in mice without PH was not mitogenic to hepatocytes in vivo. Rather, Hyper-IL-6, but not IL-6, markedly increased HGF-induced hepatocyte mitosis. This cooperative effect correlated with greater resistance of HIL-6 than IL-6 to HGF-mediated reduction of AKT activation, rather than changes in STAT3 or MAPK s…
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Determined serum IL-6 levels agree with previously reported values after PHx (1-2 ng/mL) and LPS treatment (175 ng/mL) of mice.
“Determined serum levels agree with previously reported values after PHx (1–2 ng/mL; Nechemia-Arbely et al., 2011; Yin et al., 2011) and LPS treatment (175 ng/mL; Piao et al., 2013) of mice.”
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 Nechemia-Arbely et al., 2011
Cites
Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice
Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furth, E. E., Poli, V., & Taub, R. (1996) · Science · doi:10.1126/science.274.5291.1379 · Cited by 1,536 · see citing works
Michalopoulos, G. K. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21172 · Cited by 1,384 · see citing works
Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice
Blindenbacher, A., Wang, X., Langer, I., Savino, R., Terracciano, L., & Heim, M. H. (2003) · Hepatology · doi:10.1053/jhep.2003.50378 · Cited by 202 · cited 2× · see citing works
“IL-6 expression, which dramatically increases shortly following PH [4], appears to be critical to the early onset of liver regeneration and has been shown to mediate both pro-mitotic and pro-survival activities within the regenerative process [5–8], although, the specific role of IL-6 in the mitotic response remains c…”
BackgroundTrautwein, C., Rakemann, T., Niehof, M., Rose-John, S., & Manns, M. (1996) · Gastroenterology · doi:10.1053/gast.1996.v110.pm8964411 · Cited by 131 · see citing works
Self-citationCombined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration
Peters, M., Blinn, G., Jostock, T., Schirmacher, P., Büschenfelde, K. M. Z., Galle, P. R., & Rose–John, S. (2000) · Gastroenterology · doi:10.1053/gast.2000.20236 · Cited by 129 · see citing works
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New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
Self-citationIL‐6 Trans‐signaling Controls Liver Regeneration After Partial Hepatectomy
Fazel Modares, N., Polz, R., Haghighi, F., Lamertz, L., Behnke, K., Zhuang, Y., Kordes, C., Häussinger, D., Sorg, U. R., Pfeffer, K., et al. (2019) · Hepatology · doi:10.1002/hep.30774 · Cited by 113 · see citing works
Self-citationThe double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
Wang, M.-J., Zhang, H.-L., Chen, F., Guo, X.-J., Liu, Q.-G., & Hou, J. (2024) · Experimental Hematology & Oncology · doi:10.1186/s40164-024-00527-1 · Cited by 84 · see citing works
“IL-6 can also activate PI3K/AKT and YAP/ Notch pathways independent of the STAT3 pathway to promote hepatocyte compensatory proliferation and liver regeneration [13, 20].”
BackgroundThe Regenerative Activity of Interleukin-6
Galun, E., & Rose-John, S. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-308-4_4 · Cited by 34 · see citing works
Self-citationSobotta, S., Raue, A., Huang, X., Vanlier, J., Jünger, A., Bohl, S., Albrecht, U., Hahnel, M. J., Wolf, S., Mueller, N. S., et al. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00775 · Cited by 28 · see citing works
“Determined serum levels agree with previously reported values after PHx (1–2 ng/mL; Nechemia-Arbely et al., 2011; Yin et al., 2011) and LPS treatment (175 ng/mL; Piao et al.”
BackgroundResultSelf-citation
- Authors
- Nechemia-Arbely, Y., Shriki, A., Denz, U., Drucker, C., Scheller, J., Raub, J., Pappo, O., Rose-John, S., Galun, E., & Axelrod, J. H.
- Affiliations
- Hadassah Medical Center (IL)
- Christian-Albrechts-Universität zu Kiel (DE)
- NewYork–Presbyterian Hospital (US)
- Corresponding author
- Axelrod, Jonathan H.
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 54
- Issue
- 5
- Pages
- 922-929
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W1967723169
- Cited by
- 42
- References
- 5
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 2 · 2017: 2 · 2016: 5 · 2015: 3 · 2014: 1 · 2013: 3 · 2012: 3
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Keywords
- interleukin-6, IL-6 trans-signaling, soluble IL-6 receptor, liver regeneration, partial hepatectomy, hepatocyte mitosis, hepatocyte growth factor, PI3K/Akt signaling, sgp130Fc, hyper-IL-6, STAT3, MAPK signaling, cell cycle entry
- MeSH terms
- Animals, Hepatectomy, Liver Regeneration, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mitosis, Transfection, Signal Transduction, Interleukin-6, Gene Expression, Phosphatidylinositol 3-Kinases, Receptors, Interleukin-6, Mitogen-Activated Protein Kinases, Hepatocytes, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice
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