title: Blunting Autoantigen-induced FOXO3a Protein Phosphorylation and Degradation Is a Novel Pathway of Glucocorticoids for the Treatment of Systemic Lupus Erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting multiple organs. Glucocorticoids (GCs), the potent anti-inflammatory drugs, remain as a cornerstone in the treatment for SLE; nevertheless, their clinical efficacy is compromised by the side effects of long term treatment and resistance. To improve the therapeutic efficacy of GCs in SLE, it is important to further decipher the molecular mechanisms of how GCs exert their anti-inflammatory effects. In this investigation, FOXO3a was identified as a molecule that was down-regulated in the course of SLE. Of interest, GC treatment was found to rescue FOXO3a expression both in SLE mice and in SLE patients. Gain- and loss-of-function studies demonstrated that FOXO3a played a crucial role in GC treatment of SLE via inhibiting inflammatory responses. Further studies showed that the up-regulation of FOXO3a by GCs relied on the suppression of pI3K/AKT-mediated FOXO3a phosphorylation and the arrest of FOXO3a in the nucleus. Finally, our data revealed that FOXO3a was critical for GC-mediated inhibition of NF-κB activity, which might involve its interaction with NF-κB p65 protein. Collectively, these data indicated that FOXO3a played an important role in GC treatment of SLE by suppressing pro-inflammatory response, and targeting FOXO3a might provide a novel therapeutic strategy against SLE.
authors.affiliation: From the Institute for Immunobiology, Department of Immunology, Shanghai Medical College of Fudan University, Shanghai 200032 and.
authors.forename: Mudan
authors.initials: M
authors.lastname: Lu
authors.affiliation: the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215006, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: From the Institute for Immunobiology, Department of Immunology, Shanghai Medical College of Fudan University, Shanghai 200032 and gaobo@fudan.edu.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: From the Institute for Immunobiology, Department of Immunology, Shanghai Medical College of Fudan University, Shanghai 200032 and the Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215006, China sdxiongfd@126.com.
authors.forename: Sidong
authors.initials: S
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D002467:Cell Nucleus / Q000276:immunology; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology
chemical_list: D001324:Autoantigens; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D005938:Glucocorticoids; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: FOXO; NF-kappa B (NF-KB); autoimmune disease; glucocorticoid; phosphorylation