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Endothelial IKK β Signaling is Required for Monocyte Adhesion under Laminar Flow Conditions

2002; Elsevier BV; Volume: 34; Issue: 3 Linguagem: Inglês

10.1006/jmcc.2001.1519

1095-8584

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

Immune Response and Inflammation

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- κ B family. The serine-threonine kinase, IKK β , can mediate NF- κ B activation although several alternative pathways exist. To test whether IKK β 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 IKK β (Ad.dnIKK β ) to transduce human umbilical vein endothelial cells (HUVEC) in vitro . We found that dnIKK β expression effectively blocked NF- κ B activation as assessed by nuclear translocation of NF- κ B, I κ B degradation, and NF- κ B dependent reporter expression, without affecting activation of the other relevant signaling pathways, SAPK/JNK and p38. Furthermore, overexpression of dnIKK β 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 dnIKK β -transduced endothelial monolayers were markedly inhibited. We conclude that IKK β is necessary for the cytokine-induced inflammatory phenotype of human endothelium and endothelial recruitment of human monocytes under flow.