Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice

Introduction: The purpose of this study was to elucidate the effects of histone deacetylase inhibition on the phenotype and function of dendritic cells and on arthritis in SKG mice. Methods: Arthritis was induced in SKG mice by zymosan A injection. Trichostatin A, a histone deacetylase inhibitor, was administered and its effects on arthritis were evaluated by joint swelling and histological evaluation. Interleukin-17 production in lymph node cells was determined by an enzyme-linked immunosorbent assay (ELISA). Foxp3 expression in lymph node cells and the phenotypes of splenic dendritic cells were examined by fluorescence-activated cell sorting (FACS). Bone marrow-derived dendritic cells (BM-DC) were generated with granulocyte macrophage colony-stimulating factor. The effects of trichostatin A on cell surface molecules, cytokine production, indoleamine 2,3-dioxygenase (IDO) expression and T cell stimulatory capacity were examined by FACS, ELISA, quantitative real-time polymerase chain reaction and Western blot, and the allo-mixed lymphocyte reaction, respectively. Results: Trichostatin A, when administered before the onset of arthritis, prevented SKG mice from getting arthritis. Trichostatin A treatment also showed therapeutic effects on arthritis in SKG mice, when it was administered after the onset of arthritis. Trichostatin A treatment reduced Th17 cells and induced regulatory T cells in lymph node, and also decreased co-stimulatory molecule expression on splenic dendritic cells in vivo. In vitro, trichostatin A markedly suppressed zymosan A-induced interleukin-12 and interleukin-6 production by BM-DC and up-regulated IDO expression at mRNA and protein levels. Trichostatin A-treated BM-DC also showed less T cell stimulatory capacity. Conclusions: Histone deacetylase inhibition changes dendritic cells to a tolerogenic phenotype and ameliorates arthritis in SKG mice.