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Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115
We hypothesized that blocking the induction of proinflammatory
genes associated with endothelial cell (EC) activation, by inhibiting
the transcription factor nuclear factor 
B (NF-B), would prolong
survival of vascularized xenografts. Our previous studies have shown
that inhibition of NF-B by adenovirus-mediated overexpression of
IB
suppresses the induction of proinflammatory genes in EC.
However, IB sensitizes EC to TNF--mediated apoptosis,
presumably by suppressing the induction of the NF-B-dependent
anti-apoptotic genes A20, A1, manganese superoxide dismutase
(MnSOD), and cellular inhibitor of apoptosis 2. We report here that
adenovirus mediated expression of a dominant negative C-terminal
truncation mutant of p65/RelA (p65RHD) inhibits the induction of
proinflammatory genes, such as E-selectin, ICAM-1, VCAM-1, IL-8, and
inducible nitric oxide synthase, in EC as efficiently as does IB.
However, contrary to IB, p65RHD does not sensitize EC to
TNF--mediated apoptosis although both inhibitors suppressed the
induction of the anti-apoptotic genes A20, A1, and MnSOD equally
well. We present evidence that this difference in sensitization of EC
to apoptosis is due to the ability of p65RHD, but not IB, to
inhibit the constitutive expression of c-myc, a gene
involved in the regulation of TNF--mediated apoptosis. These data
demonstrate that it is possible to block the expression of
proinflammatory genes during EC activation by targeting NF-B,
without sensitizing EC to apoptosis and establishes the role of
c-myc in controlling induction of apoptosis during EC
activation. Finally, these data provide the basis for a potential
approach to suppress EC activation in vivo in transgenic pigs to be
used as donors for xenotransplantation.
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