Role of αvβ6 integrin in acute biliary fibrosis
Open accessAbstract
Acute biliary obstruction leads to periductal myofibroblasts and fibrosis, the origin of which is uncertain. Our study provides new information on this question in mice and humans. We show that bile duct obstruction induces a striking increase in cholangiocyte αvβ6 integrin and that expression of this integrin is directly linked to fibrogenesis through activation of transforming growth factor beta (TGF-β). Administration of blocking antibody to αvβ6 significantly reduces the extent of acute fibrosis after bile duct ligation. Moreover, in β6-null mice subjected to the injury, fibrosis is reduced by 50% relative to that seen in wild-type mice, whereas inflammation occurs to the same extent. The data indicate that αvβ6, rather than inflammation, is linked to fibrogenesis. It is known that αvβ6 binds latent TGF-β and that binding results in release of active TGFβ. Consistent with this, intracellular signaling from the TGFβ receptor is increased after bile duct ligation in wild-type mice but not in β6−/− mice, and a competitive inhibitor of the TGFβ receptor type II blocks fibrosis to the same extent as antibody to αvβ6. In a survey of human liver disease, expression of αvβ6 is increased in acute, but not chronic, biliary injury and is localized to cholangiocyte-like cells. Conclusion : Cholangiocytes respond to acute bile duct obstruction with markedly increased expression of αvβ6 integrin, which is closely linked to periductal fibrogenesis. The findings provide a rationale for the use of inhibitors of αvβ6 integrin or TGFβ for down-regulating fibrosis in the setting of acute or ongoing biliary injury.
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A feedforward mechanism involving acute phase cytokines, IL-17A, and TGF-β is responsible for fibrosis following acute tissue injury.
“suggesting a feedforward mechanism involving acute phase cytokines, IL-17A, and TGF-β is responsible for the development of fibrosis following acute tissue injury109,110,123”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
TGF-β induces IL-17A expression when produced concurrently with IL-1, IL-6, or TNF.
“TGF-β in turn induced the expression of IL-17A when produced concurrently with the pro-inflammatory cytokines IL-1, IL-6, or TNF110,121,122”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
IL-17A is a key inducer of fibrosis in several organ systems, including lung, liver, kidney, heart, and skin.
“The pro-inflammatory cytokine IL-17A was identified as a key inducer of fibrosis in several different organ systems, including the lung, liver, kidney, heart, and skin109–114”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
In bleomycin-induced pulmonary fibrosis, IL-17A produced by γδ and CD4+ T cells induced severe lung inflammation, neutrophil recruitment, and production of pro-fibrotic TGF-β.
“In a study of bleomycin-induced pulmonary fibrosis, IL-17A produced by γδ and CD4+ T cells induced severe lung inflammation, neutrophil recruitment, and production of the pro-fibrotic cytokine TGF-β110”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
IL-17A signaling has a confirmed role in fibrosis development in multiple tissues, based on IL-17A- and IL-17RA-deficient mice and neutralizing monoclonal antibodies.
“Experiments with IL-17A- and IL-17RA-deficient mice, as well as therapeutic studies with IL-17A neutralizing monoclonal antibodies confirmed a role for IL-17A signaling in the development of fibrosis in multiple tissues110–112,116–118”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
In the single-hit bleomycin pulmonary fibrosis model, the IL-1-IL-17A-TGF-β axis plays a prominent role, while type 2 cytokine signaling contributes little, despite significant upregulation of IL-4 and IL-13 in the lung.
“studies with the commonly used “single hit” bleomycin pulmonary fibrosis model revealed a prominent role for the IL-1-IL-17A-TGF-β axis but little to no contribution for type 2 cytokine signaling, despite significant upregulation of IL-4 and IL-13 in the lung110”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
There is substantial cross-regulation between IL-17A and IL-13, with marked upregulation of the opposing pathway when only one mechanism is targeted therapeutically.
“several studies have revealed substantial cross-regulation between IL-17A and IL-13110,143, with marked upregulation of the opposing pathway when only one mechanism was targeted therapeutically136,142,144,145”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [110]
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- Authors
- Wang, B., Dolinski, B. M., Kikuchi, N., Leone, D. R., Peters, M. G., Weinreb, P. H., Violette, S. M., & Bissell, M. D.
- Affiliations
- University of California, San Francisco (US)
- Biogen (United States) (US)
- Corresponding author
- Bissell, Montgomery D.
- Venue
- Hepatology
- Published
- 2007-11
- Volume
- 46
- Issue
- 5
- Pages
- 1404-1412
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC4144397
- OpenAlex
- W2161626694
- Cited by
- 163
- References
- 46
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 5 · 2023: 1 · 2022: 2 · 2021: 9 · 2020: 6 · 2019: 9 · 2018: 11 · 2017: 6 · 2016: 20 · 2015: 11 · 2014: 12 · 2013: 11 · 2012: 7
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Research Training Fellowship from the Howard Hughes Medical Institute (UCSF Liver Center) (R32 DK31198, P30 DK26743)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gallbladder and Bile Duct Disorders
- Keywords
- integrin αvβ6, biliary obstruction, cholangiocytes, fibrogenesis, TGF-beta, TGFBR2, latent TGF-beta activation, anti-integrin antibodies, biliary injury
- MeSH terms
- Actins, Animals, Antigens, Neoplasm, Bile Ducts, Inflammation, Liver, Liver Cirrhosis, Biliary, Mice, Inbred C57BL, Up-Regulation, Gene Expression, Integrins, Transforming Growth Factor beta, Mice, Knockout, Integrin beta Chains, Mice
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