Loss of c-REL but not NF-κB2 prevents autoimmune disease driven by FasL mutation
| Autor: | Daniel H.D. Gray, S Gerondakis, Andreas Strasser, Rajan Jain, Paul Waring, Lorraine A. O'Reilly, Ann Lin, Ulrich Siebenlist, Peter Hughes |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Fas Ligand Protein
medicine.medical_treatment Inflammation Biology medicine.disease_cause Fas ligand Autoimmunity Proinflammatory cytokine Autoimmune Diseases Mice NF-kappa B p52 Subunit medicine Animals fas Receptor Molecular Biology Autoimmune disease Mice Knockout Original Paper Autoantibody Cell Biology medicine.disease Fas receptor Proto-Oncogene Proteins c-rel Cytokine Immunology Mutation medicine.symptom Signal Transduction |
| Zdroj: | Cell death and differentiation. 22(5) |
| ISSN: | 1476-5403 |
| Popis: | FASL/FAS signaling imposes a critical barrier against autoimmune disease and lymphadenopathy. Mutant mice unable to produce membrane-bound FASL (FasL(Δm/Δm)), a prerequisite for FAS-induced apoptosis, develop lymphadenopathy and systemic autoimmune disease with immune complex-mediated glomerulonephritis. Prior to disease onset, FasL(Δm/Δm) mice contain abnormally high numbers of leukocytes displaying activated and elevated NF-κB-regulated cytokine levels, indicating that NF-κB-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-κB signaling in FasL(Δm/Δm) mice by deleting the c-Rel or NF-κB2 genes, respectively. Although the loss of NF-κB2 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(Δm/Δm)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-κB inhibition. |
| Databáze: | OpenAIRE |
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