title: Suppression of IL-12p40-related regulatory cytokines by suberoylanilide hydroxamic acid an inhibitor of histone deacetylases.
abstract: Small molecule inhibitors of histone deacetylases (HDACs) are a new class drugs used in clinical trials for the treatment of various malignancies. Emerging evidence suggest that HDAC inhibitors may also have anti-inflammatory properties, although the molecular mechanisms remain poorly defined. Our study investigates the effect of the HDACs inhibitor suberoylanilide hydroxamic acid (SAHA) on the expression of IL-12p40-related cytokines. For this purpose, human peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. IL-12p40, IL-12p35 and IL-23p19 mRNA was determined at 6 h by qRT-PCR. Cytokine levels were determined in culture supernatants at 6 and 24 h, by ELISA. SAHA significantly inhibited IL-12p40 and IL-23p19 mRNA synthesis and did not change IL-12p35 mRNA transcription. Early at 6 h, we detected significantly decreased IL-12p40 and IL-23, but not IL-12p70 protein production in cultures treated with SAHA. Results also showed that the suppression of IL-12p40-related cytokines was clearly defined at 24 h. However, this suppression was less pronounced regarding IL-12p70. The present study showed that SAHA suppressed the gene expression of IL-23p19 stronger than the expression of IL-12p35, as well as the synthesis of IL-23 compared to that of IL-12p70. We suggest that this inhibitory effect of SAHA may be beneficial during treatment of inflammatory and autoimmune diseases mediated by Th17 immune response.
authors.affiliation: a Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty , Trakia University , Bulgaria.
authors.forename: Zlatka Georgieva
authors.initials: ZG
authors.lastname: Dobreva
authors.affiliation: a Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty , Trakia University , Bulgaria.
authors.forename: Boncho Grigorov
authors.initials: BG
authors.lastname: Grigorov
authors.affiliation: a Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty , Trakia University , Bulgaria.
authors.forename: Spaska Angelova
authors.initials: SA
authors.lastname: Stanilova
mesh_terms: D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053765:Interleukin-12 Subunit p35 / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000276:immunology*; D053760:Interleukin-23 Subunit p19 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology*; D008297:Male; D012333:RNA, Messenger / Q000276:immunology; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C508858:IL12A protein, human; C500879:IL12B protein, human; C508840:IL23A protein, human; D053765:Interleukin-12 Subunit p35; D053762:Interleukin-12 Subunit p40; D053760:Interleukin-23 Subunit p19; D012333:RNA, Messenger; D000077337:Vorinostat
keywords: Cytokine; IL-12p70; IL-23; PBMC; gene expression