title: Trichostatin differentially regulates Th1 and Th2 responses and alleviates rheumatoid arthritis in mice.
abstract: OBJECTIVE
  Histone deacetylase inhibitors have shown suppressive effects on tumor growth and in some autoimmune diseases. However, the molecular mechanisms of their effects are not very clear. The purpose of this study was to investigate the effects of trichostatin A (TSA) on collagen-induced rheumatoid arthritis (CIA) in a mouse model and its underlying mechanisms.
  
  
  METHODS
  CIA was induced in DBA/1 mice with type II collagen. Paws were scored to assess disease severity. Inflammation of joints was evaluated by histological examination. Real-time PCR was used to determine cytokine mRNA levels. Cytokine production in serum and in supernatants from dendritic to T cell co-cultures was measured by ELISA. T cell proliferation was determined using [(3)H] incorporation. Intracellular cytokine staining was used to measure interferon gamma (IFN-γ)- and interleukin (IL)-4-producing T cells in splenocytes. Chromatin immunoprecipitation was used to examine histone H3 and H4 acetylation.
  
  
  RESULTS
  TSA potently suppressed the severity of arthritis and type II collagen-specific T cell responses in CIA. IFN-γ expression was high in CIA mice, but was inhibited by TSA treatment either at the same time as immunization or at the onset of arthritis manifestation. T cells from TSA-treated mice produced higher levels of IL-4 than cells from the control group. TSA predominantly suppressed Th1 cell proliferation in vitro by induction of apoptosis. In addition, TSA enhanced IL-4 gene expression of in vitro differentiated Th2 cells, and the mechanism is associated with an increased level of histone acetylation in the IL-4 gene promoter.
  
  
  CONCLUSIONS
  While TSA selectively suppresses a Th1 response by inducing apoptosis, it upregulates IL-4 expression probably by increasing histone H3 and H4 acetylation of the IL-4 gene promoter. We conclude that TSA can induce a Th1/Th2 balance in vivo and exert protective effects on CIA.
authors.affiliation: Department of Microbiology and Immunology, Medical School of Nantong University, 19 Qixiu Road, Nantong, Jiangsu, 226001, People's Republic of China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhou
authors.forename: Xing
authors.initials: X
authors.lastname: Hua
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Ding
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Bian
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007596:Joints / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058408:Th1-Th2 Balance / Q000187:drug effects*; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D015847:Interleukin-4; C012589:trichostatin A; D007371:Interferon-gamma