title: Modulation of nuclear factor-kappaB activity can influence the susceptibility to systemic lupus erythematosus.
abstract: Autoimmune diseases, such as systemic lupus erythematosus (SLE), result from deficiencies in self-antigen tolerance processes, which require regulated dendritic cell (DC) function. In this study we evaluated the phenotype of DCs during the onset of SLE in a mouse model, in which deletion of the inhibitory receptor FcgammaRIIb leads to the production of anti-nuclear antibodies and glomerulonephritis. Splenic DCs from FcgammaRIIb-deficient mice suffering from SLE showed increased expression of co-stimulatory molecules. Furthermore, diseased mice showed an altered function of the nuclear factor-kappaB (NF-kappaB) transcription factor, which is involved in DC maturation. Compared with healthy animals, expression of the inhibitory molecule IkappaB-alpha was significantly decreased in mice suffering from SLE. Consistently, pharmacological inhibition of NF-kappaB activity in FcgammaRIIb-deficient mice led to reduced susceptibility to SLE and prevented symptoms, such as anti-nuclear antibodies and kidney damage. Our data suggest that the occurrence of SLE is significantly influenced by alterations of NF-kappaB function, which can be considered as a new therapeutic target for this disease.
authors.affiliation: Millennium Nucleus on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile. akalergis@bio.puc.cl/kalergis@vtr.net
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
authors.forename: Mirentxu I
authors.initials: MI
authors.lastname: Iruretagoyena
authors.forename: Magaly J
authors.initials: MJ
authors.lastname: Barrientos
authors.forename: Pablo A
authors.initials: PA
authors.lastname: González
authors.forename: Andres A
authors.initials: AA
authors.lastname: Herrada
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Leiva
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gutiérrez
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Riedel
authors.forename: Susan M
authors.initials: SM
authors.lastname: Bueno
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Jacobelli
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D020672:I-kappa B Proteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D004224:Diterpenes; C499172:Fcgr2b protein, mouse; D007004:Hypoglycemic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D017452:Receptors, IgG; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C030419:andrographolide