RAGE Limits Regeneration After Massive Liver Injury by Coordinated Suppression of TNF-alpha and NF-kappaB

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2005 Feb 9

PMID 15699076

Citations 50

Authors

Guellue Cataldegirmen

Shan Zeng

Nikki Feirt

Nikalesh Ippagunta

Hao Dun

Wu Qu

Yan Lu

Ling Ling Rong

Marion A Hofmann

Thomas Kislinger

Sophia I Pachydaki

Daniel G Jenkins

Alan Weinberg

Jay Lefkowitch

Xavier Rogiers

Shi Fang Yan

Ann Marie Schmidt

Jean C Emond

Affiliations

Soon will be listed here.

Abstract

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.

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