Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver
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We generated mice carrying a STAT3 allele amenable to Cre-mediated deletion and intercrossed them with Mx-Cre transgenic mice, in which the expression of Cre recombinase can be induced by type I interferon. Interferon-induced deletion of STAT3 occurred very efficiently (more than 90%) in the liver and slightly less efficiently (about 70%) in the bone marrow. Analysis of the induction of liver acute-phase genes in response to bacterial lipopolysaccharide unequivocally identifies STAT3 as a fundamental mediator of their induction. The different degrees of defectiveness displayed by the various genes allowed us to differentiate them into three separate groups according to their degree of dependence on STAT3. Induction was totally defective for group I genes, defective at 24 h but almost normal at earlier time points for group II genes, and only slightly defective for group III genes. This division was in good agreement with the known structures of the respective promoters. We also found that the overall induction of the transcription factors C/EBP beta and -delta was only minimally defective in the absence of STAT3. Finally, even though corticosterone levels and action were found to be normal in the conditional-mutant mice, production of both proinflammatory and antiinflammatory cytokines was increased and prolonged, probably as a result of STAT3 deletion in macrophages.
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Conditional deletion of STAT3 in the liver demonstrated that STAT3 is essential for the induction of all acute phase response genes downstream of IL-6.
“Also the conditional deletion of STAT3 in the liver demonstrated that STAT3 is essential for the induction of all acute phase response genes downstream of IL-6 (14”
From STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration (2002) · cites this paper as [14]
IL-6/STAT3-dependent target genes encode the APPs Fgg, Apcs, Hp, Hpx, Hamp, and Socs3.
“IL-6/STAT3-dependent target genes encode the APPs fibrinogen-γ (Fgg), serum amyloid P (Apcs), haptoglobin (Hp), hemopexin (Hpx; Alonzi et al., 2001), hepcidin (Hamp; Wrighting and Andrews, 2006; Pietrangelo et al., 2007), as well as Socs3, the negative feedback regulator of IL-6 signaling (Starr et al., 1997; Croker et al., 2003).”
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 Alonzi et al., 2001
Hp and Hpx have previously been reported to be IL-6 responsive and STAT3-dependent.
“The APP genes Hp and Hpx were not significantly regulated in our microarray analysis (Figure 2C), but have previously been reported to be IL-6 responsive and STAT3-dependent (Alonzi et al., 2001).”
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 Alonzi et al., 2001
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References 53 · Cited by 329
- Authors
- Alonzi, T., Maritano, D., Gorgoni, B., Rizzuto, G., Libert, C., & Poli, V.
- Affiliations
- University of Dundee (GB)
- Istituto Ricerche di Biologia Molecolare Angeletti
- Corresponding author
- Poli, Valeria
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2001-03
- Volume
- 21
- Issue
- 5
- Pages
- 1621-1632
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC86708
- OpenAlex
- W2129274801
- Cited by
- 329
- References
- 53
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 13 · 2021: 15 · 2020: 10 · 2019: 10 · 2018: 9 · 2017: 11 · 2016: 16 · 2015: 18 · 2014: 16 · 2013: 14 · 2012: 6
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2001-04-15)
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- STAT3, acute phase response, liver, lipopolysaccharide, type I interferon, gene induction, promoter structure, C/EBPβ, C/EBPδ, corticosterone, cytokine production, macrophages, bone marrow
- MeSH terms
- Alleles, Animals, Base Sequence, Cell Differentiation, Cell Nucleus, Corticosterone, Crosses, Genetic, Dexamethasone, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Genotype, Glucocorticoids, Humans, Interferon Type I, Lipopolysaccharides, Liver, Macrophages, Male, Mice, Transgenic, Models, Genetic, Molecular Sequence Data, Promoter Regions, Genetic, Time Factors, Transcription Factors, Viral Proteins, Blotting, Western, Trans-Activators, Cytokines, Gene Deletion, Integrases, MAP Kinase Signaling System, CCAAT-Enhancer-Binding Proteins, CCAAT-Enhancer-Binding Protein-beta, STAT3 Transcription Factor, Mice, Rats, CCAAT-Enhancer-Binding Protein-delta
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