Loss of c-REL but not NF-kappaB2 prevents autoimmune disease driven by FasL mutation
- O'Reilly, LA; Hughes, P; Lin, A; Waring, P; Siebenlist, U; Jain, R; Gray, DH; Gerondakis, S; Strasser, A;
Publication Year 2015, Volume 22, Issue #5, Page 767-78
- Journal Title
- Cell Death Differ
- Publication Type
- Journal Article
- FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasLDeltam/Deltam), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasLDeltam/Deltam mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-kappaB-regulated cytokine levels, indicating that NF-kappaB-dependent inflammation may be a key pathological driver in this multifaceted autoimmune disease. We tested this hypothesis by genetically impairing canonical or non-canonical NF-kappaB signaling in FasLDeltam/Deltam mice by deleting the c-Rel or NF-kappaB2 genes, respectively. Although the loss of NF-kappaB2 reduced the levels of inflammatory cytokines and autoantibodies, the impact on animal survival was minor due to substantially accelerated and exacerbated lymphoproliferative disease. In contrast, a marked increase in lifespan resulting from the loss of c-REL coincided with a striking reduction in classical parameters of autoimmune pathology, including the levels of cytokines and antinuclear autoantibodies. Notably, the decrease in regulatory T-cell numbers associated with loss of c-REL did not exacerbate autoimmunity in FasLDeltam/Deltamc-rel-/- mice. These findings indicate that selective inhibition of c-REL may be an attractive strategy for the treatment of autoimmune pathologies driven by defects in FASL/FAS signaling that would be expected to circumvent many of the complications caused by pan-NF-kappaB inhibition.Cell Death and Differentiation advance online publication, 31 October 2014; doi:10.1038/cdd.2014.168.
- WEHI Research Division(s)
- Molecular Genetics Of Cancer
- PubMed ID
- Publisher's Version
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2014-11-14 01:50:10Last Modified: 2015-11-10 12:20:06