Journal
ONCOTARGET
Volume 8, Issue 29, Pages 47184-47194Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.17586
Keywords
IRF5; systemic lupus erythematosus; HDAC inhibitors; Trichostatin A; p300
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Funding
- National Natural Science Foundation of China [81170661, 81300023, 81500013]
- Specialized Research Fund for the Doctoral Program of Higher Education [20113234110010]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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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-alpha, and Sp1 were significantly increased in childhood-onset SLE, as seen on quantitative realtime PCR, and the expression of Sp1 and IFN-alpha 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-alpha and IL-6 in differentiated THP1-cells. 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.
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