부산대학교 도서관

Summary: Signal transducer and activator of transcription 1 (STAT‐1) gain‐of‐function (GOF) mutations cause chronic mucocutaneous candidiasis (CMC), a disease associated with Candida albicans and Staphylococcus aureus infection. Patients suffer from dysegulated immune responses due to aberrant cell programming and function. We investigated the effect of inhibitory molecules targeting histone deacetylases (HDACi) on the immune responses of peripheral blood mononuclear cells (PBMCs) of healthy controls and patients with CMC towards microbes relevant for CMC. PBMCs cells were pretreated with HDACi and challenged with C. albicans or S. aureus. Innate and adaptive cytokines were measured in cell culture supernatants by enzyme‐linked immunosorbent assay (ELISA). We assessed the effect of HDAC inhibitors on T helper type 1 (Th1) and Th17 cells and measured STAT‐1 and STAT‐3 phosphorylation using flow cytometry. Panobinostat, a pan‐HDAC inhibitor, strongly inhibits innate and adaptive cytokines upon challenge with C. albicans or S. aureus. Specific inhibitors (entinostat or RGFP966) also had a tendency to lower production of most innate cytokines in CMC patient cells. Entinostat and RGFP966 increased the production of interleukin (IL)‐22 specifically after S. aureus challenge in patient cells. In healthy and control cells, entinostat and RGFP966 treatment down‐regulated STAT‐1 phosphorylation while pSTAT‐3 levels remained stable. HDACi modulate cytokine production in response to C. albicans and S. aureus. Pan‐inhibitors lower overall cytokine production, whereas specific inhibitors confer a selective effect. Entinostat and RGFP966 are promising therapeutic candidates to treat STAT‐1 GOF due to their capacity to restore IL‐22 production and decrease STAT‐1 phosphorylation; however, their inhibition of innate cytokines poses a possible risk to secondary infections. For patients suffering from chronic mucocutaneous candidiasis (CMC), inhibitors of histone deacetylases (HDAC) are increasingly appreciated as a promising therapeutic strategy. In light of this proposition, we tested the effect of different HDAC inhibitor classes on the immune response of peripheral blood mononuclear cells to micro‐organisms most relevant to CMC patients, Candida albicans and Staphylococcus aureus. Here we describe for the first time distinct effects of discrete HDAC inhibitor classes on stimulus‐driven cytokine production, and we identify the specific class I HDAC inhibitor, Entinostat, as a promising candidate for further investigation. [ABSTRACT FROM AUTHOR]