Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity.
OBJECTIVE
Histone deacetylases (HDAC) modulate gene transcription and chromatin assembly by modifying histones at the posttranscriptional level. HDAC inhibitors have promising antitumor activity and are presently explored in clinical studies. Cumulating evidence in animal models of immune disorders also suggests immunosuppressive properties for these small molecules, although the underlying mechanisms remain at present poorly understood. Here, we have evaluated the effects of two HDAC inhibitors currently in clinical use, sodium valproate and MS-275, on human monocyte-derived DCs.


METHODS
DCs were generated from monocytes through incubation with granulocyte macrophage colony-stimulating factor and interleukin-4. DC maturation was induced by addition of polyinosinic-polycytidylic acid. DC phenotype, immunostimulatory capacity, cytokine secretion, and migratory capacity were determined by flow cytometry, mixed leukocyte reaction, ELISA, and Transwell migration assay, respectively. Nuclear translocation of RelB, IFN regulatory factor (IRF)-3, and IRF-8 were determined by immunoblotting.


RESULTS
HDAC inhibition skews DC differentiation by preventing the acquisition of the DC hallmark CD1a and by affecting the expression of costimulation and adhesion molecules. In addition, macrophage inflammatory protein-3beta/chemokine, motif CC, ligand 19-induced migration, immunostimulatory capacity, and cytokine secretion by DCs are also profoundly impaired. The observed defects in DC function on exposure to HDAC inhibitors seem to reflect the obstruction of signaling through nuclear factor-kappaB, IRF-3, and IRF-8.


CONCLUSIONS
HDAC inhibitors exhibit strong immunomodulatory properties in human DCs. Our results support the evaluation of HDAC inhibitors in inflammatory and autoimmune disorders.
Nencioni
Alessio
A
Department of Internal Medicine, University of Genoa, Genoa, Italy.
Beck
Julia
J
Werth
Daniela
D
Grünebach
Frank
F
Patrone
Franco
F
Ballestrero
Alberto
A
Brossart
Peter
P
D021581:Active Transport, Cell Nucleus; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007107:Immune System; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051841:Transcription Factor RelB / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D000099185:Interferon Regulatory Factor-8
D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007166:Immunosuppressive Agents; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D011725:Pyridines; D051841:Transcription Factor RelB; D014635:Valproic Acid; D000099185:Interferon Regulatory Factor-8; C497593:RELB protein, human; C118739:entinostat