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(Circulation Research. 2003;92:371.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Glucose Regulates Monocyte Adhesion Through Endothelial Production of Interleukin-8

Suseela Srinivasan, Michael Yeh, Eric C. Danziger, Melissa E. Hatley, Anna E. Riggan, Norbert Leitinger, Judith A. Berliner, Catherine C. Hedrick

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.

Correspondence to Catherine C. Hedrick, PhD, Division of Endocrinology and Metabolism, University of Virginia, 415 Lane Rd, MR-5, Rm G123, PO Box 801394, Charlottesville, VA 22908. 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 ß₁ integrin on the HAEC surface, suggesting that both activate the ₅ß₁ integrin complex on the endothelial surface. The ₅ß₁ 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 ₅ß₁ integrin complex on HAECs.

Key Words: interleukin-8 • diabetes • endothelium • AP-1 • carbohydrate response element

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