Intrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis C
Abstract
Background & aims Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. Methods Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. Results We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. Conclusions Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.
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Tregs can paradoxically promote HSC activation through TGF-β-dependent signaling and IL-8 induction, facilitating fibrogenesis.
“While Tregs secrete anti-inflammatory cytokines like IL-10, IL-35, and TGF-β (Dikiy and Rudensky 2023), they can paradoxically promote HSC activation through TGF-β-dependent signaling pathway and IL-8 induction, thereby facilitating fibrogenesis (Dewidar et al. 2019; Langhans et al. 2013; Zhu et al. 2015).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Langhans et al. 2013
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- Authors
- Langhans, B., Krämer, B., Louis, M., Nischalke, H. D., Hüneburg, R., Staratschek-Jox, A., Odenthal, M., Manekeller, S., Schepke, M., Kalff, J., Fischer, H.-P., Schultze, J. L., & Spengler, U.
- Affiliations
- University of Bonn (DE)
- University of Cologne (DE)
- Helios Hospital Siegburg (DE)
- Corresponding author
- Langhans, Bettina
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 59
- Issue
- 2
- Pages
- 229-235
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W2083850987
- Cited by
- 89
- References
- 52
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 8 · 2017: 7 · 2016: 7 · 2015: 8 · 2014: 6 · 2013: 4
- FWCI
- 5.17
- 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 › Hepatology › Hepatitis C virus research
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Keywords
- chronic hepatitis C, regulatory T cells, CD4+ Foxp3+ T cells, interleukin-8, liver fibrosis, hepatic stellate cells, stellate cell activation, GARP, TGF-β1, TIMP-1, MMP-2, MCP-1
- MeSH terms
- Adult, Aged, Female, Fibrosis, Humans, Liver, Male, Middle Aged, Biomarkers, Up-Regulation, Interleukin-8, Disease Progression, Hepatitis C, Chronic, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Hepatic Stellate Cells, Young Adult, Adaptive Immunity
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