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,
*
Division of Immunology, Department of Medicine, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021; Departments of
Microbiology and
Medicine, Boston University School of Medicine, Boston, MA 02118; and
Center for Immunology, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455
The NF-
B/Rel transcription factor family has been shown to
protect many cell types from apoptotic signals. However, it is not
known whether NF-B is required for all survival pathways and whether
each NF-B 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-B/Rel members are
required for protecting cells from different types of apoptotic
signals.
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