Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic Kupffer cells

Aim: Liver fibrosis develops when chronic liver injury stimulates cells in the liver to produce mediators that activate hepatic stellate cells and stimulate them to secrete collagen. Recent studies suggest that the hypoxia-regulated transcription factor, hypoxia-inducible factor-1 alpha, is essential for upregulation of profibrotic mediators, such as platelet-derived growth factor, in the liver during the development of liver fibrosis. What remains unknown, however, is the cell type-specific regulation of profibrotic mediators by hypoxia-inducible factors. Accordingly, in the present study the hypothesis tested was that hypoxia-inducible factors regulate production of profibrotic mediators by hypoxic Kupffer cells. Methods: Kupffer cells were isolated from control mice and hypoxia-inducible factor-1 beta-deficient mice and exposed to room air or 1% oxygen (i.e. hypoxia). Levels of profibrotic mediators were quantified by real-time polymerase chain reaction. Results: Exposure of Kupffer cells isolated from control mice to 1% oxygen activated hypoxia-inducible factor-1 alpha, and increased mRNA levels of platelet-derived growth factor-B, vascular endothelial growth factor, angiopoietin-1 and monocyte chemotactic protein-1. Upregulation of all of these mediators by hypoxia was prevented in Kupffer cells isolated from hypoxia-inducible factor-1 beta-deficient mice. Conclusion: Results from these studies suggest that hypoxia-inducible factors are critical regulators of profibrotic mediator production by hypoxic Kupffer cells.