IL-6-STAT3 signaling and premature senescence
Open accessAbstract
Cytokines play several roles in developing and/or reinforcing premature cellular senescence of young cells. One such cytokine, interleukin-6 (IL-6), regulates senescence in some systems in addition to its known functions of immune regulation and promotion of tumorigenesis. In this review, we describe recent advances in studies on the roles of IL-6 and its downstream signal transducer and activator of transcription 3 (STAT3) in regulating premature cellular senescence. IL-6/sIL-6Rα stimulation forms a senescence-inducing circuit involving the STAT3-insulin-like growth factor-binding protein 5 (IGFBP5) as a key axis triggering and reinforcing component in human fibroblasts. We describe how cytokines regulate the process of senescence by activating STAT3 in one system and anti-senescence or tumorigenesis in other systems. The roles of other STAT members in premature senescence also will be discussed to show the multiple mechanisms leading to cytokine-induced senescence.
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STAT3 undergoes post-translational modifications including methylation, acetylation, ubiquitination, ISGylation, and SUMOylation.
“In addition to tyrosine phosphorylation, STAT3 also undergoes a variety of other post-translational modifications, including methylation, acetylation, ubiquitination, IFN-stimulated gene (ISG)-ylation, and small ubiquitin-related modifiers (SUMOs)-conjugation (SUMOylation) (Kojima et al., 2013; You et al., 2015; Zouein et al., 2015; Avalle and Poli, 2018; Hu et al., 2018) with various effects on”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Kojima et al., 2013
The IL-6 Receptor System and Its Signaling Pathways section (page not supplied) describes STAT3 methylation at Lys140, and its Figure 2 caption states that STAT3 is acetylated at multiple lysines. Our copy does not substantiate the other listed modifications—ubiquitination, ISGylation, or SUMOylation—of STAT3. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSenescence was induced by treatment with SASP factor IL-6, increasing SA-β-Gal activity and p21 expression, while decreasing autophagic flux and inducing the mTOR signalling pathway.
“Senescence was induced by treatment with SASP factor IL-6 [53], increasing SA-β-Gal activity and p21 expression, while decreasing autophagic flux and inducing the mTOR signalling pathway.”
From Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy (2019) · cites this paper as [53]
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References 88 · Cited by 170
- Authors
- Kojima, H., Inoue, T., Kunimoto, H., & Nakajima, K.
- Affiliations
- Osaka City University (JP)
- Tottori University (JP)
- Corresponding author
- Nakajima, Koichi
- Venue
- JAK-STAT
- Publisher
- Informa UK Limited
- Published
- 2013-10-16
- Volume
- 2
- Issue
- 4
- Pages
- e25763
- ISSN
- 2162-3988 (ISSN-L)
- 2162-3996
- PMC
- PMC3876432
- OpenAlex
- W1997372802
- Cited by
- 170
- References
- 88
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 18 · 2023: 13 · 2022: 16 · 2021: 22 · 2020: 16 · 2019: 15 · 2018: 8 · 2017: 18 · 2016: 11 · 2015: 3 · 2014: 8 · 2013: 1
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAK-STAT (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- interleukin-6, STAT3 signaling, IGFBP-5, fibroblasts, anti-senescence, carcinogenesis, JAK/STAT signaling
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