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.