Abstract
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.
Highlights
Interferon regulatory factor 5 (IRF5) plays an important role in the induction of type I interferons (IFNs) and proinflammatory cytokines interleukin (IL)-6, IL-12, and tumor necrosis factor-alpha (TNF-α), and is involved in innate and adaptive immunity [1,2,3]
We demonstrated that levels of mRNA expression of IRF5, IFN-α, and Sp1 were significantly increased in childhood-onset systemic lupus erythematosus (SLE), as seen on quantitative realtime PCR, and the expression of Sp1 and IFN-α was positively correlated with IRF5
To examine the expression levels of Sp1 and IFN-α and determine whether the expression of Sp1 or IFN-α correlate with the expression of IRF5, we extracted total RNA from peripheral blood mononuclear cells (PBMCs) of subjects with childhood-onset SLE and healthy controls to analyze their expression by quantitative real-time PCR
Summary
Interferon regulatory factor 5 (IRF5) plays an important role in the induction of type I interferons (IFNs) and proinflammatory cytokines interleukin (IL)-6, IL-12, and tumor necrosis factor-alpha (TNF-α), and is involved in innate and adaptive immunity [1,2,3]. Numerous joint linkage and genome-wide association studies have identified that there are robust associations between IRF5 SNPs and SLE, and that IRF5 high-risk variants play a critical role in the pathogenesis of SLE [6,7,8]. Besides SLE, IRF5 is involved in the pathogenesis of other immune diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome, and inflammatory bowel disease [12,13,14]. These studies were conducted in adult patients with SLE, and there is little known of the relationship between IRF5 and childhood-onset SLE
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