Glutathione depletion inhibits lipopolysaccharide-induced intercellular adhesion molecule 1 synthesis.
Cellular redox status is known to regulate a number of biological processes, including the activation of inflammatory genes. Our previous studies demonstrated that thiol depletion using diethyl maleate (DEM) reduced neutrophil sequestration in animal models of inflammation, an effect primarily mediated by impaired upregulation of the adhesion molecule, ICAM-1. The present studies were performed to discern the mechanism whereby DEM prevents LPS-induced ICAM-1 expression in human umbilical vein endothelial cells. DEM caused a time- and concentration-dependent inhibition of ICAM-1 expression in LPS-stimulated HUVEC by blocking induction of gene transcription. Interestingly, DEM had little effect on the degradation of the inhibitory protein IkappaB-alpha, but rather appeared to prevent translocation of the transcription factor NF-kappaB into the nucleus. Readdition of glutathione following DEM treatment restored the ability of LPS to induce NF-kappaB translocation and ICAM-1 synthesis. DEM plus LPS caused synergistic induction of heme oxygenase-1 (HO-1), suggesting its role in the inhibitory effects of DEM. However, HO-1 was shown to be neither sufficient nor necessary for the anti-inflammatory effects of glutathione depletion. These studies illustrate that thiol depletion may represent a potential therapy for inflammation, exerting its effects via a distinct mechanism on cell signaling pathways.
Szászi
Katalin
K
Department of Surgery, University Health Network and University of Toronto, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
Jones
Julia J
JJ
Nathens
Avery B
AB
Lo
Ai-Yen
AY
Marsden
Philip A
PA
Kapus
András
A
Rotstein
Ori D
OD
D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D005978:Glutathione / Q000172:deficiency* / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008298:Maleates / Q000494:pharmacology; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D021381:Protein Transport; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D008298:Maleates; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C014476:diethyl maleate; D005978:Glutathione; D010100:Oxygen