Complement has been implicated in liver repair after toxic injury. Here, we demonstrate that complement components are essential for liver regeneration, and mediate their effect by interacting with key signaling networks that promote hepatocyte proliferation. C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy. Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution. Interception of C5a receptor signaling resulted in suppression of IL-6/TNFα induction and lack of C3 and C5a receptor stimulation attenuated nuclear factor–κB/STAT-3 activation after hepatectomy. These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration.
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15 September 2003
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September 15 2003
The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration
Christoph W. Strey,
Christoph W. Strey
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Maciej Markiewski,
Maciej Markiewski
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Dimitrios Mastellos,
Dimitrios Mastellos
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Ruxandra Tudoran,
Ruxandra Tudoran
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Lynn A. Spruce,
Lynn A. Spruce
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Linda E. Greenbaum,
Linda E. Greenbaum
2Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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John D. Lambris
John D. Lambris
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Christoph W. Strey
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Maciej Markiewski
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Dimitrios Mastellos
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Ruxandra Tudoran
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Lynn A. Spruce
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Linda E. Greenbaum
2Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104
John D. Lambris
1Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
Address correspondence to John D. Lambris, Dept. of Pathology and Laboratory Medicine, Protein Chemistry Laboratory, University of Pennsylvania, 401 Stellar Chance/Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5765; Fax: (215) 573-8738; email: [email protected]
Abbreviations used in this paper: BrdU, 5-bromo-2′-deoxyuridine; C5aR, C5a receptor; C5aRa, C5a receptor antagonist; NF, nuclear factor; PHx, partial hepatectomy.
C.W. Strey, M. Markiewski, and D. Mastellos contributed equally to this work.
Received:
March 10 2003
Revision Received:
July 24 2003
Accepted:
July 24 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (6): 913–923.
Article history
Received:
March 10 2003
Revision Received:
July 24 2003
Accepted:
July 24 2003
Citation
Christoph W. Strey, Maciej Markiewski, Dimitrios Mastellos, Ruxandra Tudoran, Lynn A. Spruce, Linda E. Greenbaum, John D. Lambris; The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration . J Exp Med 15 September 2003; 198 (6): 913–923. doi: https://doi.org/10.1084/jem.20030374
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