Endothelial IKKβ signaling is required for monocyte adhesion under laminar flow conditions

Steffen E Meiler, Rebecca R. Hung, Robert E. Gerszten, Jacopo Gianetti, Ling Li, Takashi Matsui, Michael A. Gimbrone, Anthony Rosenzweig

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Endothelial activation induces expression of pro-inflammatory molecules that are thought to play an important role in atherogenesis through enhanced vascular monocyte recruitment. Many pro-inflammatory endothelial signals are transcriptionally regulated by members of the NF-κB family. The serine-threonine kinase, IKKβ, can mediate NF-κB activation although several alternative pathways exist. To test whether IKKβ is necessary for cytokine activation of human vascular endothelium and endothelial recruitment of human monocytes under laminar flow, we constructed a recombinant adenoviral vector carrying a dominant negative mutant of IKKβ (Ad.dnIKKβ) to transduce human umbilical vein endothelial cells (HUVEC) in vitro. We found that dnIKKβ expression effectively blocked NF-κB activation as assessed by nuclear translocation of NF-κB, IκB degradation, and NF-κB dependent reporter expression, without affecting activation of the other relevant signaling pathways, SAPK/JNK and p38. Furthermore, overexpression of dnIKKβ in TNF-α-stimulated HUVEC blocked induction of the surface adhesion molecules E-selectin, ICAM-1, and VCAM-1. Under simulated physiologic flow conditions, both firm adhesion and rolling of human peripheral monocytes on dnIKKβ-transduced endothelial monolayers were markedly inhibited. We conclude that IKKβ is necessary for the cytokine-induced inflammatory phenotype of human endothelium and endothelial recruitment of human monocytes under flow.

Original languageEnglish (US)
Pages (from-to)349-359
Number of pages11
JournalJournal of molecular and cellular cardiology
Volume34
Issue number3
DOIs
StatePublished - Mar 1 2002
Externally publishedYes

Keywords

  • Adenoviral gene transfer
  • Adhesion molecules
  • Inflammation
  • Monocytes
  • Vascular endothelium

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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