Dobreva Zlatka Georgieva, Grigorov Boncho Grigorov, Stanilova Spaska Angelova
a Department of Molecular Biology, Immunology and Medical Genetics, Medical Faculty , Trakia University , Bulgaria.
Immunopharmacol Immunotoxicol. 2016 Aug;38(4):281-5. doi: 10.1080/08923973.2016.1188940. Epub 2016 May 31.
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.
组蛋白去乙酰化酶（HDACs）小分子抑制剂是一类用于多种恶性肿瘤治疗临床试验的新型药物。新出现的证据表明，HDAC抑制剂可能也具有抗炎特性，尽管其分子机制仍不清楚。我们的研究调查了HDAC抑制剂辛二酰苯胺异羟肟酸（SAHA）对IL-12p40相关细胞因子表达的影响。为此，用人外周血单个核细胞（PBMC）在有或无SAHA的情况下用脂多糖（LPS）和C3bgp进行刺激。在6小时时通过定量逆转录聚合酶链反应（qRT-PCR）测定IL-12p40、IL-12p35和IL-23p19信使核糖核酸（mRNA）。在6小时和24小时时通过酶联免疫吸附测定（ELISA）测定培养上清液中的细胞因子水平。SAHA显著抑制IL-12p40和IL-23p19 mRNA的合成，并且不改变IL-12p35 mRNA的转录。在6小时时，我们在经SAHA处理的培养物中检测到IL-12p40和IL-23蛋白产生显著减少，但IL-12p70没有减少。结果还表明，在24小时时IL-12p40相关细胞因子的抑制作用很明显。然而，这种抑制作用在IL-12p70方面不太明显。本研究表明，SAHA对IL-23p19基因表达的抑制作用强于IL-12p35，并且与IL-12p70相比，对IL-23合成的抑制作用更强。我们认为，SAHA的这种抑制作用在由Th17免疫反应介导的炎症和自身免疫性疾病治疗期间可能是有益的。
