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

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

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Acrylamides / pharmacology*
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cell Line
  • Gene Expression Regulation
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Humans
  • Lung / drug effects*
  • Lung / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Myocytes, Smooth Muscle / metabolism
  • Phenylenediamines / pharmacology*
  • Pneumonia / metabolism
  • Respiratory Mucosa / metabolism
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic

Substances

  • Acrylamides
  • Anti-Inflammatory Agents
  • Histone Deacetylase Inhibitors
  • Histones
  • Phenylenediamines
  • RGFP966
  • Transcription Factor RelA
  • Hdac1 protein, mouse
  • Hdac2 protein, mouse
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases
  • histone deacetylase 3