Suppression of proinflammatory cytokine production by suberoylanilide hydroxamic acid an inhibitor of histone deacetylases

Abstract

ABSRACTChromatin remodeling by acetylation and deacetylation of histones play an essential role in regulation of the gene expression. The opposing activity of two type enzymes controls the acetylation degree of the chromatin structure. Histone acetylation by acetyltransferases leads to relaxed chromatin structure and this process supports the transcription. Deacetylation by histone deacetylases (HDACs) compact the chromatin structure and favors gene silence. Small molecule inhibitors of HDACs are a new class drugs used in clinical trials for the treatment of various malignancies. Emerging evidence suggest that HDAC inhibitors may have also anti-inflammatory properties, although the molecular mechanisms remain poorly defined. Our study investigates the effect of the HDACs inhibitor Suberoylanilide Hydroxamic Acid (SAHA) on Th1 and Th17 polarizing cytokines IL-12p40 and IL-23. For this purpose, human peripheral blood mononuclear cells (PBMC) were stimulated with LPS and C3bgp with or without SAHA. Cytokine production was determined in culture supernatants at 6 and 24 h, by ELISA. IL-12p40 and IL-23 synthesis was measured in stimulated PBMC at 6 and increased at 24 h. Early at 6 h, we detected significantly decreased IL-12p40 and IL-23 production in stimulated PBMC treated with SAHA and this tendency was retained at 24 h. In conclusion, our results demonstrated that the inhibition of HDACs by SAHA leads to suppression of IL-12p40 and IL-23 regardless of stimuli used. The downregulating effect of SAHA on the proinflammatory cytokine production may be beneficial during treatment of chronic inflammatory diseases which progression is mediated by Th17 immune response.