Abstract
Macrophages play an integral role in the development of liver fibrosis by releasing mediators, such as platelet-derived growth factor-B (PDGF-B) and transforming growth factor-β1, which stimulate hepatic stellate cell proliferation, chemotaxis, and collagen production. However, the mechanism by which chronic liver injury stimulates macrophages to release these mediators is not completely understood. We tested the hypothesis that chronic liver injury activates hypoxia-inducible factor (HIF) transcription factors in macrophages that regulate the production of mediators that promote fibrosis. To test this hypothesis, Cre/lox technology was used to generate myeloid cell-specific HIF-1α or HIF-1β knockout mice. When these mice were subjected to bile duct ligation (BDL), levels of α-smooth muscle actin and type I collagen in the liver were reduced compared with those of mice with normal levels of HIFs. The deficiency of HIFs in macrophages did not affect liver injury or inflammation after BDL but reduced PDGF-B mRNA and protein, suggesting that HIF activation in macrophages may promote fibrosis by regulating the production of PDGF-B. Consistent with a role for HIFs in liver fibrosis in cholestatic liver disease, nuclear HIF-1α protein was present in macrophages, hepatocytes, and fibroblasts in the livers from patients with primary biliary cirrhosis and primary sclerosing cholangitis. These studies demonstrate that HIFs are important regulators of profibrotic mediator production by macrophages during the development of liver fibrosis and suggest that HIFs may be a novel therapeutic target for the treatment of chronic liver disease in patients.
Footnotes
This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK073566]; the National Institutes of Health National Center for Research Resources [Grant P20-RR016475]; and the National Institutes of Health, Center of Biomedical Research Excellence [Grant P20-RR021940] as well as the Molecular Biology Core and the Histology Core supported by the Center of Biomedical Research Excellence grant.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- PDGF-B
- platelet-derived growth factor-B
- α-SMA
- α-smooth muscle actin
- ALT
- alanine aminotransferase
- Ang
- angiopoietin
- BDL
- bile duct ligation
- FGF-2
- fibroblast growth factor-2
- HIF
- hypoxia-inducible factor
- KC
- keratinocyte-derived chemotactic factor
- MCP-1
- monocyte chemotactic protein-1
- MIP-2
- macrophage inflammatory protein-2
- PAI-1
- plasminogen activator inhibitor-1
- PBC
- primary biliary cirrhosis
- PBS
- phosphate-buffered saline
- PCR
- polymerase chain reaction
- PP
- periportal
- PSC
- primary sclerosing cholangitis
- TGF-β
- transforming growth factor-β
- TNF-α
- tumor necrosis factor-α
- VEGF-A
- vascular endothelial growth factor-A.
- Received October 20, 2011.
- Accepted January 20, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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