The Journal of Experimental Medicine
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Published 15 September 2003. doi:10.1084/jem.20030374
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© Rockefeller University Press, 0022-1007/2003/9/913 $5.00
The Journal of Experimental Medicine, Volume 198, Number 6, 913-923

The Proinflammatory Mediators C3a and C5a Are Essential for Liver Regeneration

Christoph W. Strey1, Maciej Markiewski1, Dimitrios Mastellos1, Ruxandra Tudoran1, Lynn A. Spruce1, Linda E. Greenbaum2 and John D. Lambris1

1 Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
2 Division of Gastroenterology, Department of 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: lambris{at}mail.med.upenn.edu

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/TNF{alpha} induction and lack of C3 and C5a receptor stimulation attenuated nuclear factor–{kappa}B/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.

Key Words: complement • anaphylatoxins • NF-{kappa}B • STAT-3 • IL-6


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