HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity

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• 作者：Niek G.J. Leus^a ; Petra E. van der Wouden^a ; Thea van den Bosch^a ; Wouter T.R. Hooghiemstra^a ; Maria E. Ourailidou^a ; Loes E.M. Kistemaker^c ; Rainer Bischoff^b ; Reinoud Gosens^c ; Hidde J. Haisma^a ; Frank J. Dekker^a ; ^{f.j.dekker@rug.nl" class="auth_mail" title="E-mail the corresponding author}
• 关键词：RGFP966 (PubChem CID ; 56650312) ; N ; N-Dimethylformamide (PubChem CID ; 6228) ; Suberoylanilide hydroxamic acid (PubChem CID ; 5311)
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：108
• 期：Complete
• 页码：58-74
• 全文大小：3828 K

文摘

The increasing number of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathology of COPD. Here, we applied the pharmacological HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was observed. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymatic activity of HDAC 3. Taken together, our findings indicate that pharmacological HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases.