Opposing roles of RAGE and Myd88 signaling in extensive liver resection Journal Article
| Authors: | Zeng, S.; Zhang, Q. Y.; Huang, J.; Vedantham, S.; Rosario, R.; Ananthakrishnan, R.; Yan, S. F.; Ramasamy, R.; DeMatteo, R. P.; Emond, J. C.; Friedman, R. A.; Schmidt, A. M. |
| Article Title: | Opposing roles of RAGE and Myd88 signaling in extensive liver resection |
| Abstract: | In extensive liver resection secondary to primary or metastatic liver tumors, or in living donor liver transplantation, strategies to quell deleterious inflammatory responses and facilitate regeneration are essential. The receptor for advanced glycation endproducts (RAGE) and myeloid differentiating factor 88 (Myd88) are implicated in the inflammatory response. To establish the contributions of RAGE vs. Myd88 signaling in extensive liver resection, we probed the effect of RAGE and/or Myd88, the latter primarily a key transducer of major toll-like receptors and also implicated in interleukin-1 (Il1) signaling, in a murine model of extensive (85%) hepatectomy. We report that, although Myd88 is thoroughly essential for survival via regulation of NF-κB and TNF-α, deletion of RAGE significantly improved survival compared to wild-type, Myd88-null, or RAGE-null/Myd88-null mice. RAGE opposes Myd88 signaling at multiple levels: by suppression of p65 levels, thereby reducing activation of NF-κB and consequent production of cyclin D1, and by suppression of Il6-mediated phosphorylation of Stat3, thereby down-regulating Pim1 and suppressing the hyperplastic response. Further, RAGE-dependent suppression of glyoxalase1, a detoxification pathway for pre-AGEs, enhances AGE levels and suppresses Il6 action. We conclude that blockade of RAGE may rescue liver remnants from the multiple signals that preclude adaptive proliferation triggered primarily by Myd88 signaling pathways. © FASEB. |
| Keywords: | signal transduction; protein phosphorylation; gene deletion; nonhuman; cell proliferation; mouse; animals; mice; mice, knockout; animal tissue; hepatocytes; mus; stat3 protein; apoptosis; gene expression; animal experiment; inflammation; immunoglobulin enhancer binding protein; mice, inbred c57bl; tumor necrosis factor alpha; rna, messenger; nf-kappa b; murinae; liver resection; stat3 transcription factor; hepatectomy; immunity, innate; down regulation; upregulation; proliferation; liver cell; liver regeneration; up-regulation; cyclin d1; myeloid differentiation factor 88; toll like receptor; receptors, immunologic; interleukin 1; toll-like receptor 4; advanced glycation end product; synaptotagmin i; advanced glycation end product receptor; protein kinase pim 1; proto-oncogene proteins c-pim-1; pim1; stat 3 phosphorylation; glyoxalase; nuclear factor-?b; glycosylation end products, advanced |
| Journal Title: | FASEB Journal |
| Volume: | 26 |
| Issue: | 2 |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 2012-02-01 |
| Start Page: | 882 |
| End Page: | 893 |
| Language: | English |
| DOI: | 10.1096/fj.11-192997 |
| PROVIDER: | scopus |
| PUBMED: | 22075646 |
| PMCID: | PMC3365861 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 March 2012" - "CODEN: FAJOE" - "Source: Scopus" |
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