Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses
Open accessAbstract
Hepatic fibrosis represents the generalized response of the liver to injury and is characterized by excessive deposition of extracellular matrix. The cellular basis of this process is complex and involves interplay of many factors, of which cytokines are prominent. We have identified divergent fibrosing responses to injury among mouse strains and taken advantage of these differences to examine and contrast T helper (Th)-derived cytokines during fibrogenesis. Liver injury was induced with carbon tetrachloride, fibrosis was quantitated, and Th1/Th2 cytokine mRNAs measured. Liver injury in BALB/c mice resulted in severe fibrosis, whereas C57BL/6 mice developed comparatively minimal fibrosis. Fibrogenesis was significantly modified in T and B cell-deficient BALB/c and C57BL/6 severe combined immunodeficient (SCID) mice compared with wild-type counterparts, suggesting a role of Th subsets. Fibrogenic BALB/c mice exhibited a Th2 response during the wounding response, whereas C57BL/6 mice displayed a Th1 response, suggesting that hepatic fibrosis is influenced by different T helper subsets. Moreover, mice lacking interferon γ, which default to the Th2 cytokine pathway, exhibited more pronounced fibrotic lesions than did wild-type animals. Finally, shifting of the Th2 response toward a Th1 response by treatment with neutralizing anti-interleukin 4 or with interferon γ itself ameliorated fibrosis in BALB/c mice. These data support a role for immune modulation of hepatic fibrosis and suggest that Th cytokine subsets can modulate the fibrotic response to injury.
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In inbred mouse strains, different genetic makeup determines susceptibility to liver fibrosis, ranging from fibrosis resistance in A/J mice to high susceptibility in BALB/c.
“A similar phenomenon, the precise mechanism of which is poorly understood, has been reported in inbred mouse strains, where different genetic makeup determines susceptibility to liver fibrosis. This ranges from fibrosis resistance in A/J mice to high susceptibility in the BALB/c strain2,3.”
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“In contrast to the type 2 cytokine IL-4 signaling as a profibrotic mediator, IFN-γ has been characterized as an anti-fibrotic cytokine in the context of CCl4-mediated liver fibrosis (26, 27).”
BackgroundLebeaupin, C., Donahue, K. L., Lal, S., Christensen, S. M., Asano, S., Wadsworth, M. H., Bound, K., De, S., McMahon, J., Schlerman, F., et al. (2025) · bioRxiv (preprint) · doi:10.64898/2025.12.17.694415
- Authors
- Shi, Z., Wakil, A. E., & Rockey, D. C.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Rockey, Don C.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-09-30
- Volume
- 94
- Issue
- 20
- Pages
- 10663-10668
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC23440
- OpenAlex
- W1983273975
- Cited by
- 310
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 7 · 2019: 12 · 2018: 9 · 2017: 8 · 2016: 8 · 2015: 20 · 2014: 9 · 2013: 13 · 2012: 13
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Crohn's and Colitis Foundation of America
- American Liver Foundation
- Crohn's and Colitis Foundation
- National Institutes of Health (7k08dk002124-06)
- Genentech
- University of California, San Francisco
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-50574, R01DK050574, DK 02124)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- liver fibrosis, liver injury, T helper cells, Th1/Th2 balance, cytokines, strain differences, BALB/c mice, C57BL/6 mice, carbon tetrachloride, interferon-gamma, IL-4, immunomodulation, extracellular matrix deposition, SCID mice
- MeSH terms
- Animals, Liver, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, RNA, Messenger, Species Specificity, Wound Healing, Cytokines, Mice, SCID, Th1 Cells, Th2 Cells, Mice
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