A20 inhibits NF-kappaB activation in endothelial cells without sensitizing to tumor necrosis factor-mediated apoptosis.
Expression of the NF-kappaB-dependent gene A20 in endothelial cells (EC) inhibits tumor necrosis factor (TNF)-mediated apoptosis in the presence of cycloheximide and acts upstream of IkappaBalpha degradation to block activation of NF-kappaB. Although inhibition of NF-kappaB by IkappaBalpha renders cells susceptible to TNF-induced apoptosis, we show that when A20 and IkappaBalpha are coexpressed, the effect of A20 predominates in that EC are rescued from TNF-mediated apoptosis. These findings place A20 in the category of "protective" genes that are induced in response to inflammatory stimuli to protect EC from unfettered activation and from undergoing apoptosis even when NF-kappaB is blocked. From a therapeutic perspective, genetic engineering of EC to express an NF-kappaB inhibitor such as A20 offers the mean of achieving an anti-inflammatory effect without sensitizing the cells to TNF-mediated apoptosis.
Ferran
C
C
Department of Surgery, Center for Immunobiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA 02215, USA.
Stroka
D M
DM
Badrichani
A Z
AZ
Cooper
J T
JT
Wrighton
C J
CJ
Soares
M
M
Grey
S T
ST
Bach
F H
FH
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology* / Q000502:physiology*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D016328:NF-kappa B / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha