RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB

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 glycat...

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Published inThe Journal of experimental medicine Vol. 201; no. 3; p. 473
Main Authors Cataldegirmen, Guellue, Zeng, Shan, Feirt, Nikki, Ippagunta, Nikalesh, Dun, Hao, Qu, Wu, Lu, Yan, Rong, Ling Ling, Hofmann, Marion A, Kislinger, Thomas, Pachydaki, Sophia I, Jenkins, Daniel G, Weinberg, Alan, Lefkowitch, Jay, Rogiers, Xavier, Yan, Shi Fang, Schmidt, Ann Marie, Emond, Jean C
Format Journal Article
LanguageEnglish
Published United States 07.02.2005
Subjects
Animals
Apoptosis - physiology
Cell Lineage
Cell Proliferation
Cytokines - metabolism
Gene Expression Regulation
Hepatectomy
Humans
Liver - cytology
Liver - metabolism
Liver - pathology
Liver Regeneration
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
NF-kappa B - metabolism
Receptor for Advanced Glycation End Products
Receptors, Immunologic
Survival Rate
Tumor Necrosis Factor-alpha - metabolism
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Summary: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-kappaB, 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.
ISSN:0022-1007