Inhibition of NF-kappa B by pyrrolidine dithiocarbamate blocks endothelial cell activation.
Endothelial cell activation is achieved by the rapid, protein synthesis-independent induction of a characteristic set of genes. Because of the abundance of binding sites for the transcription factor NF-kappa B in the regulatory region of the aforementioned genes, we hypothesized that this factor might play a key role. Reactive oxygen intermediates act as second messengers in the activation of NF-kappa B. We have used the antioxidant pyrrolidine dithiocarbamate to analyze the effect of NF-kappa B inhibition on TNF alpha-induced EC activation in vitro. We show that pyrrolidine dithiocarbamate strongly reduces the TNF alpha-mediated induction of E-selectin, VCAM-1, ICAM-1, PAI-1, tissue factor, IL-8 and I kappa B-alpha. We present evidence identifying NF-kappa B as a central of EC activation. Therefore, this factor may represent a prime target for therapeutic intervention in pathologic conditions associated with EC activation such as allo- and xenograft rejection, atherosclerosis, ischemic reperfusion injury and vasculitis.
Ferran
C
C
Sandoz Center for Immunobiology, New England Deaconess Hospital, Harvard Medical School, Boston, MA 02215, USA.
Millan
M T
MT
Csizmadia
V
V
Cooper
J T
JT
Brostjan
C
C
Bach
F H
FH
Winkler
H
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000235:genetics; D019040:E-Selectin; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016758:Genes, jun; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics; D006861:Hydrogen Peroxide / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D013552:Swine; D013859:Thiocarbamates / Q000494:pharmacology*; D013879:Thioredoxins / Q000235:genetics
D000975:Antioxidants; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases