Glucose regulates monocyte adhesion through endothelial production of interleukin-8

Circ Res. 2003 Mar 7;92(4):371-7. doi: 10.1161/01.RES.0000061714.74668.5C. Epub 2003 Feb 13.

Abstract

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 beta1 integrin on the HAEC surface, suggesting that both activate the alpha5beta1 integrin complex on the endothelial surface. The alpha5beta1 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-kappaB 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 alpha5beta1 integrin complex on HAECs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Gene Expression Regulation / drug effects
  • Glucose / pharmacology*
  • Humans
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Monocytes / cytology
  • Monocytes / drug effects*
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Thenoyltrifluoroacetone / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Uncoupling Agents / pharmacology

Substances

  • Interleukin-8
  • RNA, Messenger
  • Reactive Oxygen Species
  • Transcription Factor AP-1
  • Uncoupling Agents
  • Thenoyltrifluoroacetone
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Glucose