c-Rel Is Required for the Protection of B Cells from Antigen Receptor-Mediated, But Not Fas-Mediated, Apoptosis

Abstract

The NF-κB/Rel transcription factor family has been shown to protect many cell types from apoptotic signals. However, it is not known whether NF-κB is required for all survival pathways and whether each NF-κB member plays a unique or a redundant role. Here we describe the results of studies on the role of c-Rel in survival. Mature B cells from c-Rel−/− mice exhibit defects in survival, including sensitivity to Ag receptor-mediated apoptosis as well as increased sensitivity to ionizing radiation and glucocorticoids. Transgene expression of Bcl-xL, a c-Rel target gene, rescues c-Rel−/− B cells from their survival defects. Thus, c-Rel-dependent survival pathways are crucial for protection from apoptotic signals that target the mitochondrial pathway. Despite a lack of Bcl-xL, c-Rel−/− B cells can still be rescued from Fas-mediated apoptosis via B cell receptor signaling. The Fas apoptosis inhibitor molecule and FLICE inhibitory protein (c-FLIP) proteins are up-regulated normally in c-Rel−/− B cells, and these two molecules may play a more physiological role in the Fas pathway. Furthermore, unlike the TNF sensitivity of RelA−/− fibroblasts, c-Rel-deficient fibroblasts are refractory to TNF-mediated cell death. Thus, c-Rel is dispensable for protection against death receptor-mediated apoptosis. Taken together, our data suggest that distinct NF-κB/Rel members are required for protecting cells from different types of apoptotic signals.

NF-κB and the immune response

“…In such cases, it is expected that B-cell responses are more dependent on members of the canonical pathway that have well-documented roles in TLR signaling, or BCR signaling (as discussed above). For example, c-Rel-deficient B cells are highly sensitive to apoptosis following BCR cross-linking (Grumont et al, 1998(Grumont et al, , 1999Owyang et al, 2001). As mentioned above, p50 and p50/pRelA double knockout B cells are deficient in responses to TI stimulation.…”

NF-κB in immunobiology

“…In such cases it is expected that B-cell responses are more dependent on members of the canonical pathway that have well-documented roles in TLR and BCR signaling. For example, c-Rel-deficient B cells are highly sensitive to apoptosis following BCR cross-linking [187][188][189]. As mentioned above, p50 and p50/RelA doubleknockout B cells are deficient in responses to TI stimulation.…”

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

“…In contrast, PCD via necrosis is independent of caspases and is typically associated with breakdown of the plasma membrane, organelle swelling and nuclear degradation that is accompanied by the release of nuclear factors like high mobility group box 1 (HMGB1) that trigger a potent inflammatory response (reviewed in Lotze and Tracey, 2005;Zeh and Lotze, 2005). NF-kB is commonly cytoprotective toward PCD caused by apoptosis or necrosis and its prosurvival activity has been observed in response to a variety of death-inducing stimuli like the proinflammatory cytokine TNFa, ultraviolet (UV) radiation, anticancer agents and B-cell receptor crosslinking (Wu et al, 1996;Grumont et al, 1998;Wang et al, 1998;van Antwerp et al, 1998;Owyang et al, 2001). However, NF-kB can promote cell death in response to certain stimuli and in certain cells (reviewed in Baldwin, 2001;Karin and Lin, 2002;Kucharczak et al, 2003).…”