Anti-Fibrotic Actions of Interleukin-10 against Hypertrophic Scarring by Activation of PI3K/AKT and STAT3 Signaling Pathways in Scar-Forming Fibroblasts
Open accessAbstract
BACKGROUND: The hypertrophic scar (HS) is a serious fibrotic skin condition and a major clinical problem. Interleukin-10 (IL-10) has been identified as a prospective scar-improving compound based on preclinical trials. Our previous work showed that IL-10 has anti-fibrotic effects in transforming growth factor (TGF)-β1-stimulated fibroblasts, as well as potential therapeutic benefits for the prevention and reduction of scar formation. However, relatively little is known about the mechanisms underlying IL-10-mediated anti-fibrotic and scar-improvement actions. OBJECTIVE: To explore the expression of the IL-10 receptor in human HS tissue and primary HS fibroblasts (HSFs), and the molecular mechanisms contributing to the anti-fibrotic and scar-improvement capabilities of IL-10. METHODS: Expression of the IL-10 receptor was assessed in HS tissue and HSFs by immunohistochemistry, immunofluorescence microscopy, and polymerase chain reaction analysis. Primary HSFs were treated with IL-10, a specific phosphatidylinositol 3 kinase (PI3K) inhibitor (LY294002) or a function-blocking antibody against the IL-10 receptor (IL-10RB). Next, Western blot analysis was used to evaluate changes in the phosphorylation status of AKT and signal transducers and activators of transcription (STAT) 3, as well as the expression levels of fibrosis-related proteins. RESULTS: HS tissue and primary HSFs were characterized by expression of the IL-10 receptor and by high expression of fibrotic markers relative to normal controls. Primary HSFs expressed the IL-10 receptor, while IL-10 induced AKT and STAT3 phosphorylation in these cells. In addition, LY294002 blocked AKT and STAT phosphorylation, and also up-regulated expression levels of type I and type III collagen (Col 1 and Col 3) and alpha-smooth muscle actin (α-SMA) in IL-10-treated cells. Similarly, IL-10RB reduced STAT3/AKT phosphorylation and blocked the IL-10-mediated mitigation of fibrosis in HSFs. CONCLUSION: IL-10 apparently inhibits fibrosis by activating AKT and STAT3 phosphorylation downstream of the IL-10 receptor, and by facilitating crosstalk between the PI3K/AKT and STAT3 signal transduction pathways.
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In vitro studies have shown that blocking signaling of IL-10 in fibroblasts may decrease keloid scar formation.
“A role for these therapies in cutaneous fibrosis remains to be explored, though in vitro studies have shown that blocking signaling of the related cytokine IL-10 in fibroblasts may decrease keloid scar formation [102].”
From Immunology of Wound Healing (2018) · cites this paper as [102]
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References 43 · Cited by 116
- Authors
- Shi, J., Li, J., Guan, H., Cai, W., Bai, X., Fang, X., Hu, X., Wang, Y., Wang, H., Zheng, Z., Su, L., Hu, D., & Zhu, X.
- Affiliations
- Xijing Hospital (CN)
- Corresponding author
- Hu, Dahai
- Zhu, Xiongxiang
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-05-30
- Volume
- 9
- Issue
- 5
- Pages
- e98228
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4039501
- OpenAlex
- W2000343974
- Cited by
- 116
- References
- 43
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 17 · 2022: 7 · 2021: 14 · 2020: 16 · 2019: 9 · 2018: 11 · 2017: 8 · 2016: 9 · 2015: 1 · 2014: 3 · 2013: 1
- FWCI
- 7.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Natural Science Foundation of China (81171811, XJZT12D01, 81272098)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
- Keywords
- hypertrophic scars, IL-10, antifibrotic effect, scar formation, PI3K/Akt signaling, STAT3 signaling, IL-10 receptor, collagen expression, alpha-smooth muscle actin, TGF-β1, LY294002, skin fibrosis
- MeSH terms
- Enzyme Activation, Fibroblasts, Fibrosis, Humans, Skin, Signal Transduction, Interleukin-10, Cicatrix, Hypertrophic, STAT3 Transcription Factor, Proto-Oncogene Proteins c-akt, Receptors, Interleukin-10, Phosphatidylinositol 3-Kinase
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