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Open Access Research article

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

Kenta Misaki12, Akio Morinobu1*, Jun Saegusa2, Shimpei Kasagi1, Masaaki Fujita1, Yoshiaki Miyamoto1, Fumichika Matsuki2 and Shunichi Kumagai12

Author Affiliations

1 Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine. 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

2 Department of Evidence-based Laboratory Medicine, Kobe University Graduate School of Medicine. 7-5-2, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

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Arthritis Research & Therapy 2011, 13:R77  doi:10.1186/ar3339

Published: 18 May 2011

Abstract

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.