© 1998 American Heart Association, Inc.
Original Contributions |
Inhibition of Tumor Necrosis Factor-
– and Interleukin-1–Induced Endothelial E-Selectin Expression by Thiol-Modifying Agents
From the German Institute of Human Nutrition Potsdam-Rehbrücke (B.F., R.B.-F.) and the Institute of Nutritional Science, University of Potsdam (C.M., R.B.-F.), Potsdam-Rehbrücke, Germany.
Correspondence to Dr Regina Brigelius-Flohé, German Institute of Human Nutrition Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, D-14558 Bergholz-Rehbrücke, Germany. E-mail flohe{at}www.dife.de
Abstract—The expression of
endothelial-leukocyte adhesion molecules has been
postulated to be regulated by redox-sensitive events. Tumor necrosis
factor- (TNF-)– and interleukin-1 (IL-1)–induced E-selectin
expression was analyzed after pretreating human umbilical vein
endothelial cells with different thiol-modifying
agents, ie, diamide, phenylarsine oxide,
N-ethylmaleimide, and diethyl maleate. E-selectin
protein expression was quantified by indirect
immunofluorescence. All compounds suppressed the
cytokine-induced E-selectin expression in a
concentration-dependent manner, whereas the antioxidant
N-acetylcysteine showed no effect. The
inhibitory effect of diamide (100 µmol/L, 1 hour)
was reversible within 6 hours when the cells were allowed to recover
before application of cytokines. Reversibility was strongly
delayed when cells were deprived of glutathione by buthionine
sulfoximine pretreatment. Glutathione depletion alone did not influence
cytokine-induced E-selectin expression. Analysis of
cellular glutathione status showed a 3-fold increase in oxidized
glutathione after diamide treatment. Monochlorobimane labeling also
revealed a decrease in total cellular thiols. During recovery, the
glutathione status was restored within 1 hour, whereas total thiol
content and E-selectin expression needed at least 6 hours to return to
baseline. Complete inhibition of E-selectin expression by the vicinal
thiol blocker phenylarsine oxide (0.5 µmol/L) was reversed by
dithiols like dithiothreitol or dimercaptopropanol, but not by the
monothiol 2-mercaptoethanol. These data suggest that proteins with
essential thiols, most probably vicinal thiols. are involved in the
IL-1– and TNF-–mediated induction of E-selectin. These thiols must
be in the reduced state; oxidation or other modification thereof
attenuates or abolishes the cells' response to the cytokines.
Key Words: E-selectin • tumor necrosis factor- • interleukin-1 • diamide • phenylarsine oxide
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