IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors

Autor: Jin Shu, Li-Li Zhuang, Jun Qian, Ling Li, Lan-Bo Zhou, Guo-Ping Zhou, Hai-Guo Yu, Rui Jin, Zhi-Dan Fan, Lu-Lu Wang
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Transcription
Genetic
Sp1 Transcription Factor
Gene Expression
Autoimmunity
p300
P300-CBP Transcription Factors
Cell Line
03 medical and health sciences
systemic lupus erythematosus
HDAC inhibitors
Genes
Reporter
IRF5
Gene expression
medicine
Humans
Lupus Erythematosus
Systemic
p300-CBP Transcription Factors
Age of Onset
Child
Promoter Regions
Genetic
Autoantibodies
Histone Acetyltransferases
Regulation of gene expression
biology
Interleukin-6
Tumor Necrosis Factor-alpha
Histone acetyltransferase
Histone Deacetylase Inhibitors
030104 developmental biology
Trichostatin A
Gene Expression Regulation
Oncology
Case-Control Studies
Child
Preschool
Interferon Regulatory Factors
Immunology
Cancer research
biology.protein
Female
Histone deacetylase
Chromatin immunoprecipitation
Protein Binding
Research Paper
medicine.drug
Zdroj: Oncotarget
ISSN: 1949-2553
DOI: 10.18632/oncotarget.17586
Popis: Interferon regulatory factor 5 (IRF5) plays a critical role in the induction of type I interferon, proinflammatory cytokines and chemokines, and participates in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). However, the relationship between IRF5 and childhood-onset SLE remains elusive. In the present study, we demonstrated that levels of mRNA expression of IRF5, IFN-α, and Sp1 were significantly increased in childhood-onset SLE, as seen on quantitative real-time PCR, and the expression of Sp1 and IFN-α was positively correlated with IRF5. In addition to being used as antitumor drugs, a number of histone deacetylase inhibitors (HDACi) display potent anti-inflammatory properties; however, their effects on IRF5 expression remain unclear. In this study, we identified that HDACi trichostatin A (TSA) and histone acetyltransferase (HAT)-p300 downregulated IRF5 promoter activity, mRNA expression, and protein level, whereas the HAT-p300/CBP-associated factor had no effect. Moreover, TSA inhibited the production of TNF-α and IL-6 in differentiated THP-1cells. Furthermore, chromatin immunoprecipitation assays revealed that TSA inhibited DNA binding of Sp1, RNA polymerase II, HDAC3, and p300 to the core promoter region of IRF5. Our results suggest that HDACi may have therapeutic potential in patients with autoimmune diseases such as SLE through repression of IRF5 expression.
Databáze: OpenAIRE
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