| First Author | O'Reilly LA | Year | 2015 |
| Journal | Cell Death Differ | Volume | 22 |
| Issue | 5 | Pages | 767-78 |
| PubMed ID | 25361085 | Mgi Jnum | J:258532 |
| Mgi Id | MGI:6142078 | Doi | 10.1038/cdd.2014.168 |
| Citation | O'Reilly LA, et al. (2015) Loss of c-REL but not NF-kappaB2 prevents autoimmune disease driven by FasL mutation. Cell Death Differ 22(5):767-78 |
| abstractText | FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL(Deltam/Deltam)), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL(Deltam/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 FasL(Deltam/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 FasL(Deltam/Deltam)c-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. |
