turn, activates the IκB kinase (IKK) and IKKβ-dependent activation of NF-κB
(Malinin et al., 1997; Kelliher et al., 1998; Scheidereit, 1998). TRAF2 and RIP also
stimulate JNK/AP-1 via activation of apoptosis signal regulating kinase (ASK)1
(Nishitoh et al., 1998). Cells from TRAF2 gene knockout mice or transgenic mice
expressing a dominant negative TRAF2 mutant fail to activate JNK in response to
TNF, but have only slight defects in TNF-induced activation of NF-κB (Lee et al.,
1997; Yeh et al., 1997). In contrast, RIP-deficient cells remain capable of activating
JNK but lack the ability to activate NF-κB in response to TNF (Kelliher et al., 1998).
Therefore, RIP is essential for TNF-induced activation of NF-κB, while TRAF2 is
required for signaling the activation of JNK. In addition to inducing expression of
diverse proinflammatory and immunomodulatory genes, NF-κB promotes the
expression of genes that protect cells from TNF-induced apoptosis (discussed below).
Since the proapoptotic activity of TNF-α is opposed by the concurrent expression
of antiapoptotic NF-κB target genes, the ability of TNF-α to induce apoptosis
requires the inhibition of NF-κB. The differential ability to activate NF-κB may
explain why TNF-α, unlike FasL, rarely triggers apoptosis unless new protein
synthesis is simultaneously blocked (Baud and Karin, 2001).
In addition to protecting cells from the latent death-signaling arm of TNFR1,
TNF-α-induced activation of NF-κB promotes the expression of a host of
proinflammatory and immunomodulatory genes that mediate the biologic function
of this cytokine. In the absence of the protection conferred by NF-κB, TNF-α loses
its native function in the immune response and, instead, acquires a proapoptotic role.
The mid-gestational lethality of RelA-/-, IKKβ-/-, or IKKγ-/- mice results from the
extensive hepatocyte apoptosis induced by the production of TNF-α by
hematopoietic progenitors that are resident in the fetal liver. The massive liver
apoptosis resulting from embryonic deficiency of RelA is completely reversed by the
concurrent deficiency of TNFR1 or TNF-α in DKO mice (Doi et al., 1999;
Rosenfeld et al., 2000; Alcamo et al., 2001). NF-κB also protects lymphoid cells from
death receptor-induced apoptosis during the immune response (Van Parijs et al.,
1996a). Activation of NF-κB by co-stimulation of lymphocytes mediates cell survival
and clonal proliferation, while inhibition of NF-κB by IκB mutants promotes
activation-induced apoptosis of T cells, and loss of CD8+T cells in the thymus. As
shall be discussed later, NF-κB-mediated protection of cells from death receptor-
induced apoptosis plays an instrumental role in regulating the immune response.
Molecular mechanisms by which NF-κB regulates death receptor-
induced apoptosisNF-κB is a critical determinant of the expression of genes that modulate death
receptor-induced apoptosis. NF-κB promotes the expression of a number of survival
factors, including the caspase-8/FLICE inhibitor (c-FLIP), members of the inhibitor
of apoptosis (IAP) family (c-IAP1, C-IAP2, XIAP), TNFR-associated factors (TRAF1
and TRAF2), and the Bcl-2 homologs, A1 (also known as Bfl-1) and Bcl-xL. As
discussed above, these proteins serve to interrupt different steps along the death
16 GENETICS OF APOPTOSIS