Role of NF-kappaB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by lipopolysaccharide.
We investigated the role of NF-kappaB activation by the bacterial product lipopolysaccharide (LPS) in inducing caveolin-1 (Cav-1) expression and its consequence in contributing to the leakiness of the endothelial barrier. We observed that LPS challenge of human lung microvascular endothelial cells induced concentration- and time-dependent increases in expression of Cav-1 mRNA and protein. The NEMO (NF-kappaB essential modifier binding domain)-binding domain peptide (IkB kinase (IKK)-NEMO-binding domain (NBD) peptide), which prevents NF-kappaB activation by inhibiting the interaction of IKKgamma with the IKK complex, blocked LPS-induced Cav-1 mRNA and protein expression. Knockdown of NF-kappaB subunit p65/RelA expression with small interfering RNA also prevented LPS-induced Cav-1 expression. Caveolae open to the apical and basal plasmalemma of endothelial cells increased 2-4-fold within 4 h of LPS exposure. IKK-NBD peptide markedly reduced the LPS-induced increase in the number of caveolae as well as transendothelial albumin permeability. These observations were recapitulated in mouse studies in which IKK-NBD peptide prevented Cav-1 expression and interfered with the increase in lung microvessel permeability induced by LPS. Thus, LPS mediates NF-kappaB-dependent Cav-1 expression that results in increased caveolae number and thereby contributes to the mechanism of increased transendothelial albumin permeability.
Tiruppathi
Chinnaswamy
C
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Shimizu
Jun
J
Miyawaki-Shimizu
Kayo
K
Vogel
Stephen M
SM
Bair
Angela M
AM
Minshall
Richard D
RD
Predescu
Dan
D
Malik
Asrar B
AB
D001483:Base Sequence; D051242:Caveolin 1 / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000502:physiology*; D016133:Polymerase Chain Reaction
D051242:Caveolin 1; D017931:DNA Primers; D008070:Lipopolysaccharides; D016328:NF-kappa B