title: 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.
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.
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Niek G J
authors.initials: NG
authors.lastname: Leus
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Petra E
authors.initials: PE
authors.lastname: van der Wouden
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Thea
authors.initials: T
authors.lastname: van den Bosch
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Wouter T R
authors.initials: WTR
authors.lastname: Hooghiemstra
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ourailidou
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Loes E M
authors.initials: LE
authors.lastname: Kistemaker
authors.affiliation: Department of Analytical Biochemistry, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Rainer
authors.initials: R
authors.lastname: Bischoff
authors.affiliation: Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.affiliation: Department of Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Hidde J
authors.initials: HJ
authors.lastname: Haisma
authors.affiliation: 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.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
mesh_terms: D000107:Acetylation; D000178:Acrylamides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology*; D011014:Pneumonia / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D000178:Acrylamides; D000893:Anti-Inflammatory Agents; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D010655:Phenylenediamines; D051996:Transcription Factor RelA; D000099186:Histone Deacetylase 3; C000603861:RGFP966; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse
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)