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Advanced Glycation End Products activate MMP‐9 secretion in macrophage cells, the involvement of MAP Kinase and NF‐kappaB signaling pathways
Author(s) -
Banker Greg,
Zhang Fan,
Kent K. Craig,
Liu Bo
Publication year - 2010
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/fasebj.24.1_supplement.489.1
Subject(s) - rage (emotion) , mapk/erk pathway , glycation , matrix metalloproteinase , kinase , signal transduction , mitogen activated protein kinase , microbiology and biotechnology , nf κb , chemistry , pathogenesis , cancer research , biology , receptor , immunology , biochemistry , neuroscience
Matrix metalloproteinases (MMPs) are integral to pathogenesis of vascular diseases including abdominal aortic aneurysms (AAAs). We have previously shown that advanced glycation end products (AGEs) and their receptor RAGE are critical to AAA formation, in part through a novel function of AGEs, i.e. to induce MMP‐9 expression. The purpose of this study is to investigate the signal transduction mechanisms underlying AGE's regulation of MMP‐9. Using the RAW 264.7 macrophage cell line, we found that AGE (300 μg) activates multiple signaling pathways. The induction of all three MAP Kinases peaked between 30–60 min while the induction of NF‐κB peaked after 4 h, suggesting NFκB may be downstream of the MAP Kinases in the regulation of MMP‐9. Inhibition of ERK activity with PD098059 or UO126 (10–20 μM) and NFκB with PAO (5–20 μM) dose dependently decreased the amount of MMP‐9 induced by AGE. Inhibition of JNK with SP600125 or BI7803, however, further stimulated MMP‐9 expression induced by AGE. Similarly, inhibition of JNK potentiated the induction of MMP‐9 by TNF‐α. Taken together, our data suggest that AGE stimulates MMP‐9 expression through a mechanism involving ERK and NFκB. JNK MAP kinase seems to play a negative role in AGE signaling in macrophages. We believe that further exploration of the mechanism of AGE regulated MMP‐9 will further our understanding of the signaling network that may contribute to the pathogenesis of AAA.