title: HDAC expression and activity is upregulated in diseased lupus-prone mice.
abstract: Prior studies have shown that pan-HDAC inhibition can decrease disease in lupus mice; however, the mechanisms(s) remain to be elucidated. MRL/MpJ-Fas(lpr) (MRL/lpr) mice develop a lupus-like disease characterized by anti-dsDNA production, lymphoproliferation, and immune complex-mediated glomerulonephritis. Early- and late-disease (12 and 20weeks-of-age respectively) female MRL/lpr mice were compared to age-matched, healthy C57BL/6 mice for HDAC expression and activity in bone marrow (BM) B cells, splenic B and T cells, and glomerular cells. We found that HDAC6 was significantly overexpressed in B cells, splenic T cells and glomerular cells, whereas HDAC9 expression was significantly increased in splenic T cells, BM B cells and glomerular cells. Due to the overexpression of HDAC6, we tested whether treatment with a selective HDAC6 inhibitor (ACY-738) or a pan-HDAC inhibitor (TsA) would decrease HDAC activity. ACY-738 significantly reduced cytoplasmic HDAC activity whereas TsA significantly decreased both nuclear and cytoplasmic HDAC activity. In vitro studies in mesangial cells showed that ACY-738 increased α-tubulin and Hsp90 acetylation resulting in decreased nuclear activation of NF-κB. Treatment of pre-B cells with ACY-738 decreased the Bcl-2:Bax ratio leading to a pro-apoptotic environment. These results suggest that increased HDAC6 expression and activity contribute to SLE pathogenesis, and isoform-selective HDAC inhibitors may prove beneficial in the treatment of SLE by acetylating key signaling and transcription factors in inflammation and cell activation.
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, United States.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Regna
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, United States.
authors.forename: Miranda D
authors.initials: MD
authors.lastname: Vieson
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Gojmerac
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, United States.
authors.forename: Xin M
authors.initials: XM
authors.lastname: Luo
authors.affiliation: Wake Forest University Primate Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States; Department of Pathology/Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
authors.affiliation: Department of Biomedical Sciences & Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, United States; Edward Via College of Osteopathic Medicine, Blacksburg, VA, 24060, United States. Electronic address: chreilly@vcom.vt.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000201:enzymology; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics*; D007678:Kidney Glomerulus / Q000166:cytology / Q000201:enzymology; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology; D015854:Up-Regulation
chemical_list: D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C499033:Hdac6 protein, mouse; C486545:Hdac9 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: B cells; Glomerular cells; HDAC; SLE; T cells