Published online before print February 13, 2003, doi: 10.1161/01.RES.0000061714.74668.5C
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Submitted on March 12, 2002
Revised on January 30, 2003
Accepted on January 31, 2003
Glucose Regulates Monocyte Adhesion Through Endothelial Production of Interleukin-8
Suseela Srinivasan ;
From the Division of Cardiology (M.Y., J.A.B.), University of California Los Angeles, Los Angeles, Calif; University of Vienna (N.L.), Vienna, Austria; and Division of Endocrinology and Metabolism (S.S., E.C.D., M.E.H., A.E.R., C.C.H.), University of Virginia, Charlottesville, Va.
* To whom correspondence should be addressed. E-mail: cch6n{at}virginia.edu.
We have shown that glucose increases monocyte adhesion to human aortic endothelial cells (HAECs) in vitro.1 In the present study, we examined mechanisms by which glucose stimulates monocyte:endothelial interactions. HAECs cultured for 7 days in 25 mmol/L glucose had a 2-fold elevation in interleukin-8 (IL-8) secretion over control cells cultured in 5.5 mmol/L glucose (P<0.001). Use of a neutralizing antibody to IL-8 prevented glucose-mediated monocyte adhesion. Both glucose and IL-8 activated 
1 integrin on the HAEC surface, suggesting that both activate the 
51 integrin complex on the endothelial surface. The 51 integrin complex is important for anchoring connecting segment-1 fibronectin on the HAEC surface for monocyte adhesion. Analysis of the human IL-8 promoter revealed binding sites for NF-
B and AP-1 as well as several aligned carbohydrate response elements (also known as E-boxes). Glucose dramatically stimulated IL-8 promoter activity. Using mutated IL-8 promoter constructs and EMSA, we found that the AP-1 element and the glucose-response element were responsible for much of the glucose-mediated activation of IL-8 transcription. Interestingly, inhibition of reactive oxygen species (ROS) production through use of pharmacological uncouplers of the mitochondrial electron transport chain significantly reduced glucose-mediated induction of IL-8 expression. These data indicate that glucose regulates monocyte:endothelial interactions through stimulation of IL-8 and ROS production and activation of the 51 integrin complex on HAECs.
Key words: interleukin-8 • diabetes • endothelium • AP-1 • carbohydrate response element
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