Interleukin-6-Induced STAT3 and AP-1 Amplify Hepatocyte Nuclear Factor 1-Mediated Transactivation of Hepatic Genes, an Adaptive Response to Liver Injury
Open accessAbstract
Following hepatic injury or stress, gluconeogenic and acute-phase response genes are rapidly upregulated to restore metabolic homeostasis and limit tissue damage. Regulation of the liver-restricted insulin-like growth factor binding protein 1 (IGFBP-1) gene is dramatically altered by changes in the metabolic state and hepatectomy, and thus it provided an appropriate reporter to assess the transcriptional milieu in the liver during repair and regeneration. The cytokine interleukin-6 (IL-6) is required for liver regeneration and repair, and it transcriptionally upregulates a vast array of genes during liver growth by unknown mechanisms. Evidence for a biologic role of IL-6 in IGFBP-1 upregulation was demonstrated by increased expression of hepatic IGFBP-1 in IL-6 transgenic and following injection of IL-6 into nonfasting animals and its reduced expression in IL-6(-/-) livers posthepatectomy. In both hepatic and nonhepatic cells, IL-6 -mediated IGFBP-1 promoter activation was via an intact hepatocyte nuclear factor 1 (HNF-1) site and was dependent on the presence of endogenous liver factor HNF-1 and induced factors STAT3 and AP-1 (c-Fos/c-Jun). IL-6 acted through the STAT3 pathway, as dominant negative STAT3 completely blocked IL-6-mediated stimulation of the IGFBP-1 promoter via the HNF-1 site. HNF-1/c-Fos and HNF-1/STAT3 protein complexes were detected in mouse livers and in hepatic and nonhepatic cell lines overexpressing STAT3/c-Fos/HNF-1. Similar regulation was demonstrated…
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IGFBP-1 activation is in part regulated by IL-6 via direct interaction between STAT3, AP-1, and HNF-1 transcription factors.
“Its activation is in part regulated by IL-6 via direct interaction between STAT3, AP-1, and HNF-1 transcription factors (5”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [5]
The change in IGFBP-1 expression in STAT3 conditional-mutant livers is not as great as that seen in IL-6−/− livers.
“However, the change is not as great as that seen in the IL-6−/− livers (5”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [5]
Although STATs bind a similar DNA binding site, they may interact with co-activators or co-repressors to regulate different sets of their own downstream targets.
“Although they bind to a similar DNA binding site, STATs may interact with co-activator or co-repressor to regulate different sets of their own downstream targets (5”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [5]
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Novel insights into genetics and clinics of the HNF1A-MODY
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Molecular dissection of gp130-dependent pathways in hepatocytes during liver regeneration
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- Authors
- Leu, J. I., Crissey, M. A. S., Leu, J. P., Ciliberto, G., & Taub, R.
- Affiliations
- University of Pennsylvania (US)
- Institute of Molecular Biology and Pathology (IT)
- Corresponding author
- Taub, Rebecca
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2001-01-01
- Volume
- 21
- Issue
- 2
- Pages
- 414-424
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC86585
- OpenAlex
- W2122076953
- Cited by
- 134
- References
- 4
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 6 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 9
- FWCI
- 7.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarly Commons (University of Pennsylvania) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK19629, P01DK049210, DK 49210, P30DK50306, P30DK050306)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- interleukin-6, STAT3, AP-1, HNF1, IGFBP-1, hepatic gene transcription, liver regeneration, liver injury, glucose-6-phosphatase, transcriptional coactivation, acute phase response, gluconeogenesis, liver homeostasis
- MeSH terms
- Animals, DNA, DNA-Binding Proteins, Fibrinogen, Glucose-6-Phosphatase, Hepatectomy, Humans, Liver, Male, Nuclear Proteins, Precipitin Tests, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Transcription Factors, Tumor Cells, Cultured, Transcriptional Activation, Trans-Activators, Interleukin-6, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-fos, Mice, Knockout, Transcription Factor AP-1, Insulin-Like Growth Factor Binding Protein 1, Response Elements, STAT3 Transcription Factor, Mice, Hepatocyte Nuclear Factor 1, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta
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