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Opposing roles of RAGE and Myd88 signaling in extensive liver resection
Author(s) -
Zeng Shan,
Zhang Qing Yin,
Huang Jianzhong,
Vedantham Srinivasan,
Rosario Rosa,
Ananthakrishnan Radha,
Yan Shi Fang,
Ramasamy Ravichandran,
DeMatteo Ronald P.,
Emond Jean C.,
Friedman Richard A.,
Schmidt Ann Marie
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-192997
Subject(s) - rage (emotion) , cancer research , signal transduction , receptor , medicine , biology , immunology , microbiology and biotechnology , neuroscience
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.—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. Opposing roles of RAGE and Myd88 signaling in extensive liver resection. FASEB J. 26, 882–893 (2012). www.fasebj.org