title: Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1.
abstract: Histone deacetylase (HDAC) inhibitors reduce development of graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Administration of the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA) resulted in a significantly reduced GVHD-dependent mortality following fully major histocompatibility complex-mismatched allogeneic BMT. However, SAHA treatment did not affect T-cell activation or T-cell expansion in vitro and in vivo. Therefore, we focused on the effects of SAHA treatment on cytokine production and intracellular signaling events in vitro and in vivo following GVHD induction. Cultivation in the presence of SAHA broadly inhibited lipopolysaccharide (LPS) and alloantigen-induced cytokine/chemokine production in vitro and led also to a significant decrease in interferon-gamma and tumor necrosis factor-alpha levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and alloactivation in vitro. Induction of GVHD led to a rapid phosphorylation of STAT 1 in the liver and spleen, which was markedly reduced by SAHA treatment. In conclusion, GVHD is associated with a marked induction of phosphorylation of STAT1 in the liver and spleen, and SAHA-dependent reduction of GVHD is associated with systemic and local inhibition of phosphorylated STAT1 and blunting proinflammatory cytokine production during the initiation phase of GVHD.
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charite, Campus Buch, Humboldt University, Berlin, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Leng
authors.forename: Margarethe
authors.initials: M
authors.lastname: Gries
authors.forename: Judy
authors.initials: J
authors.lastname: Ziegler
authors.forename: Anna
authors.initials: A
authors.lastname: Lokshin
authors.forename: Paolo
authors.initials: P
authors.lastname: Mascagni
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006086:Graft vs Host Disease / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D006648:Histocompatibility; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007249:Inflammation / Q000201:enzymology / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014184:Transplantation, Homologous; D000077337:Vorinostat
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000077337:Vorinostat; D006655:Histone Deacetylases