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Biochem Pharmacol. 2016 May 15;108:58-74. doi: 10.1016/j.bcp.2016.03.010. Epub 2016 Mar 16.

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.

Author information

1
Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
2
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
3
Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
4
Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. Electronic address: f.j.dekker@rug.nl.

Abstract

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.

KEYWORDS:

HDAC inhibitors; HDACs; Inflammation; Lung disease; Lysine acetylation; N,N-Dimethylformamide (PubChem CID: 6228); NF-κB p65; RGFP966 (PubChem CID: 56650312); Suberoylanilide hydroxamic acid (PubChem CID: 5311)

PMID:
26993378
PMCID:
PMC4844503
DOI:
10.1016/j.bcp.2016.03.010
[Indexed for MEDLINE]
Free PMC Article

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