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Papers In Press, published online ahead of print May 15, 2004
CVRC, University of Virginia, Charlottesville, VA 22908
Corresponding Author: cch6n{at}virginia.edu
We have shown that chronic elevated glucose (25mM; HG) increases monocyte adhesion to human aortic endothelial cells. This increased adhesion is mediated primarily through induction of IL-8 via activation of the transcription factor AP-1 (Circ Res. 2003 92: 371). In the current study, we identified the elements in the AP-1 transcriptional complex that are activated by glucose. These elements include c-jun, c-fos, and fra-1. AP-1 is activated by cellular oxidative stress, and we have reported significant production of ROS by HG-cultured cells. We examined signaling pathways upstream of AP-1 in EC that lead to AP-1 activation by HG. EC cultured in 25mM glucose had a 2-fold increase in p38 phosphorylation compared to control NG-cultured EC. Inhibition of the p38 pathway using 5uM SB203580 significantly reduced glucose-mediated IL-8 mRNA production by 60%. Furthermore, blocking p38 pathway activation using a dominant-negative p38 construct significantly reduced glucose-mediated monocyte adhesion by 50%. Thus, glucose-stimulated monocyte adhesion is primarily regulated through phosphorylation of p38 with subsequent activation of AP-1, leading to IL-8 production. To study this pathway in the setting of diabetes, we used the db/db mouse. P38 phosphorylation was increased in diabetic db/db mice compared to control mice. We found a dramatic elevation in plasma levels of KC, the mouse ortholog of IL-8 in diabetic db/db mice (1800±100 pg/ml KC in db/db versus 300±75pg/ml in C57BL/6J control mice, p<0.0001). Inhibition of the p38 pathway in diabetic db/db mice significantly reduced monocyte adhesion by 50%. Taken together, these data indicate that chronic elevated glucose in diabetes activates the p38 MAP kinase pathway to increase inflammatory IL-8 gene induction and monocyte:endothelial adhesion.
J. Biol. Chem, 10.1074/jbc.M400753200
Submitted on January 23, 2004
Revised on May 11, 2004
Accepted on May 14, 2004
Glucose regulates interleukin-8 production in aortic endothelial cells through activation of the p38 MAP kinase pathway in diabetes
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