RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB.
RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB.
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DOI：
10.1084/jem.20040934
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发表时间：
2005-02-07
期刊：
影响因子：
--
通讯作者：
Emond JC
中科院分区：
文献类型：
--
作者：
Cataldegirmen G;Zeng S;Feirt N;Ippagunta N;Dun H;Qu W;Lu Y;Rong LL;Hofmann MA;Kislinger T;Pachydaki SI;Jenkins DG;Weinberg A;Lefkowitch J;Rogiers X;Yan SF;Schmidt AM;Emond JC
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-κB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-α 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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