Regulation of angiopoietin expression by bacterial lipopolysaccharide.
Angiopoietins are ligands for Tie-2 receptors and play important roles in angiogenesis and inflammation. While angiopoietin-1 (Ang-1) inhibits inflammatory responses, angiopoietin-2 (Ang-2) promotes cytokine production and vascular leakage. In this study, we evaluated in vivo and in vitro effects of Escherichia coli lipopolysaccharides (LPS) on angiopoietin expression. Wild-type C57/BL6 mice were injected with saline (control) or E. coli LPS (20 mg/ml ip) and killed 6, 12, and 24 h later. The diaphragm, lung, and liver were excised and assayed for mRNA and protein expression of Ang-1, Ang-2, and Tie-2 protein and tyrosine phosphorylation. LPS injection elicited a severalfold rise in Ang-2 mRNA and protein levels in the three organs. By comparison, both Ang-1 and Tie-2 levels in the diaphragm, liver, and lung were significantly attenuated by LPS administration. In addition, Tie-2 tyrosine phosphorylation in the lung was significantly reduced in response to LPS injection. In vitro exposure to E. coli LPS elicited cell-specific changes in Ang-1 expression, with significant induction in Ang-1 expression being observed in cultured human epithelial cells, whereas significant attenuation of Ang-1 expression was observed in response to E. coli LPS exposure in primary human skeletal myoblasts. In both cell types, E. coli LPS elicited substantial induction of Ang-2 mRNA, a response that was mediated in part through NF-kappaB. We conclude that in vivo endotoxemia triggers functional inhibition of the Ang-1/Tie-2 receptor pathway by reducing Ang-1 and Tie-2 expression and inducing Ang-2 levels and that this response may contribute to enhanced vascular leakage in sepsis.
Mofarrahi
Mahroo
M
Critical Care Division, Royal Victoria Hospital, 687 Pine Ave West, Montréal, Québec, Canada H3A 1A1.
Nouh
Thamir
T
Qureshi
Salman
S
Guillot
Loic
L
Mayaki
Dominique
D
Hussain
Sabah N A
SN
D042683:Angiopoietin-1 / Q000235:genetics* / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics* / Q000378:metabolism; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology; D032446:Myoblasts / Q000166:cytology / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D042787:Receptor, TIE-2 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000502:physiology*; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042682:Angiopoietins; C467628:Angpt1 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; C118117:angiopoietin 4; D042787:Receptor, TIE-2