NF-κB RelA (p65) Is Essential for TNF-α-Induced Fas Expression but Dispensable for Both TCR-Induced Expression and Activation-Induced Cell Death

Abstract

The Fas death receptor plays a key role in the killing of target cells by NK cells and CTLs and in activation-induced cell death of mature T lymphocytes. These cytotoxic pathways are dependent on induction of Fas expression by cytokines such as TNF-α and IFN-γ or by signals generated after TCR engagement. Although much of our knowledge of the Fas death pathway has been generated from murine studies, little is known about regulatory mechanisms important for murine Fas expression. To this end, we have molecularly cloned a region of the murine Fas promoter that is responsible for mediating TNF-α and PMA/PHA-induced expression. We demonstrate here that induction of Fas expression by both stimuli is critically dependent on two sites that associate with RelA-containing NF-κB complexes. To determine whether RelA and/or other NF-κB subunits are also important for regulating Fas expression in primary T cells, we used CD4 T cells from RelA−/−, c-Rel−/−, and p50−/− mice. Although proliferative responses were significantly impaired, expression of Fas and activation-induced cell death was unaffected in T cells obtained from these different mice. Importantly, we show that unlike fibroblasts, which consist primarily of RelA-containing NF-κB complexes, T cells have high levels of both RelA and c-Rel complexes, suggesting that Fas expression in T cells may be dependent on redundant functions of these NF-κB subunits.

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

“…In some of these cases, NF-kB induced expression of death-promoting genes (Table 1). These include tumor suppressor p53, the DR Fas and its ligand FasL and TNFa Shakhov et al, 1990;Wu and Lozano, 1994;Kasibhatla et al, 1998Kasibhatla et al, , 1999Matsui et al, 1998;Chan et al, 1999;Zheng et al, 2001). For instance, NF-kB induces FasL expression in T cells in response to AICD (Kasibhatla et al, 1999).…”

“…In this context, NF-kB triggered the Fas-death cascade by directly activating the expression of Fas ligand (FasL) ( Duyao et al (1990), La Rosa et al (1994) et al, 1999; Lin et al, 1999;Zheng et al, 2001). The expression of a dominant IkB molecule (IkBaM) inhibited both FasL expression and apoptosis.…”

Current insights into the regulation of programmed cell death by NF-κB

“…A few proapoptotic NF-kB transcriptional target genes appear to be involved in this effect. These proapoptotic targets include the death receptors Fas(CD95), TRAIL receptors DR4, DR5 and DR6, the death-inducing ligands FasL, TNFa and TRAIL, tumor suppressor p53, the proapoptotic multidomain Bcl-2 family member Bax and the proapoptotic alternatively spliced form of Bcl-xL, Bcl-xS Shakhov et al, 1990;Wu and Lozano, 1994;Kasibhatla et al, 1998;Matsui et al, 1998;Chan et al, 1999;Kasibhatla et al, 1999;Baetu et al, 2001;Kasof et al, 2001;RiveraWalsh et al, 2001;Siegmund et al, 2001;Zheng et al, 2001;Kim et al, 2002;Shou et al, 2002;Kucharczak et al, 2003;Chen et al, 2003b;Grimm et al, 2005). A recent example of a proapoptotic NF-kB activity is the apoptosis of cortical neurons that occurs following serum withdrawal and K þ loss, which is associated with increased levels of NF-kB and the resultant upregulation of Bcl-xS (Tao et al, 2006).…”

BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas‐mediated cell death

“…Previous reports indicate that Fas expression can be regulated by several pathways including the Ras/ERK pathway [25][26][27]. Therefore, to examine whether this signaling pathway was involved in the up-regulation of Fas-induced by BAFF in LPS-activated B cells, we evaluated the levels of phosphorylated-ERK (p-ERK) in LPS-activated B cells cultured in the presence or absence of BAFF (Fig.…”