The Journal of Experimental Medicine
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Published 7 February 2005. doi:10.1084/jem.20040934
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 3, 473-484
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ARTICLE

 RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-{alpha} and NF-{kappa}B

Guellue Cataldegirmen1, Shan Zeng1, Nikki Feirt3, Nikalesh Ippagunta1, Hao Dun1, Wu Qu2, Yan Lu2, Ling Ling Rong2, Marion A. Hofmann2, Thomas Kislinger2, Sophia I. Pachydaki2, Daniel G. Jenkins2, Alan Weinberg4, Jay Lefkowitch3, Xavier Rogiers5, Shi Fang Yan2, Ann Marie Schmidt2, and Jean C. Emond1

1 Division of Liver Diseases and Transplantation, Department of Surgery
2 Surgical Science, Department of Surgery
3 Department of Pathology, Columbia University Medical Center
4 School of Public Health, Columbia University, New York, NY 10032
5 Department of Hepatobiliary Surgery, University Hospital Eppendorf Hamburg, 20246 Hamburg, Germany

CORRESPONDENCE Jean Emond: je111{at}columbia.edu

The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-{kappa}B, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-{alpha} and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death–promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.

Abbreviations used: DN, dominant negative; EMSA, electrophoretic mobility shift assay; MP, mononuclear phagocyte; MPDDC, MP-derived DC; PCNA, proliferating cell nuclear antigen; RAGE, receptor for advanced glycation endproducts; SR, scavenger receptor promoter; sRAGE, soluble RAGE; VCAM-1, vascular cell adhesion molecule-1.

G. Cataldegirmen and S. Zeng contributed equally to this work.


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