title: The histone deacetylase inhibitors vorinostat and romidepsin downmodulate IL-10 expression in cutaneous T-cell lymphoma cells.
abstract: OBJECTIVE
  Vorinostat and romidepsin are histone deacetylase inhibitors (HDI), approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, the mechanism(s) by which these drugs exert their anti-cancer effects are not fully understood. Since CTCL is associated with immune dysregulation, we investigated whether these HDI modulated cytokine expression in CTCL cells.
  
  
  METHODS
  CTCL cell lines and primary CTCL cells were treated in vitro with vorinostat or romidepsin, or with STAT3 pathway inhibitors. Cell cycle parameters and apoptosis were analysed by propidium iodide and annexin V/propidium iodide staining respectively. Cytokine expression was analysed using QRT-PCR and elisa assays. STAT3 expression/phosphorylation and transcriptional activity were analysed using immunoblotting and transfection/reporter assays respectively.
  
  
  RESULTS
  Vorinostat and romidepsin strongly down-regulated expression of the immunosuppressive cytokine, interleukin (IL)-10, frequently overexpressed in CTCL, at both the RNA and protein level in CTCL cell lines and at the RNA level in primary CTCL cells. Vorinostat and romidepsin also increased expression of IFNG RNA and decreased expression of IL-2 and IL-4 RNA, although to a lesser extent compared to IL-10. Transient exposure to vorinostat was sufficient to suppress IL-10 secretion but was not sufficient to irreversibly commit cells to undergo cell death. STAT3 pathway inhibitors decreased production of IL-10 and vorinostat/romidepsin partially decreased STAT3-dependent transcription without effects on STAT3 expression or phosphorylation.
  
  
  CONCLUSIONS
  These results demonstrate that HDI modulate cytokine expression in CTCL cells, potentially via effects on STAT3. Immunomodulation may contribute to the clinical activity of HDI in this disease.
authors.affiliation: Southampton Cancer Research UK Centre, Cancer Sciences Division, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, UK.
authors.forename: Ce
authors.initials: C
authors.lastname: Tiffon
authors.forename: Je
authors.initials: J
authors.lastname: Adams
authors.forename: L
authors.initials: L
authors.lastname: van der Fits
authors.forename: S
authors.initials: S
authors.lastname: Wen
authors.forename: Pa
authors.initials: P
authors.lastname: Townsend
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.forename: E
authors.initials: E
authors.lastname: Hodges
authors.forename: Mh
authors.initials: M
authors.lastname: Vermeer
authors.forename: G
authors.initials: G
authors.lastname: Packham
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077337:Vorinostat; D000096743:Interferon gamma Receptor
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007155:Immunologic Factors; D016753:Interleukin-10; D017471:Receptors, Interferon; D050796:STAT3 Transcription Factor; D000077337:Vorinostat; D000096743:Interferon gamma Receptor; C494086:STAT3 protein, human; C087123:romidepsin