This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nencioni, A. Articles by Brossart, P. Search for Related Content PubMed PubMed Citation Articles by Nencioni, A. Articles by Brossart, P.

Histone Deacetylase Inhibitors Affect Dendritic Cell Differentiation and Immunogenicity

Authors' Affiliations: ¹ Department of Internal Medicine, University of Genoa, Genoa, Italy; ² Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; and ³ Department of Hematology, Oncology and Immunology, University of Tübingen, Tubingen, Germany

Requests for reprints: Peter Brossart, Department of Hematology, Oncology and Immunology, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tubingen, Germany. Phone: 49-7071-29-80625; Fax: 49-7071-29-5709; E-mail: peter.brossart{at}med.uni-tuebingen.de.

Purpose: 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.

Experimental Design: 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-3ß/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-B, 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.

This article has been cited by other articles:

				D. Bosisio, M. Vulcano, A. Del Prete, M. Sironi, V. Salvi, L. Salogni, E. Riboldi, F. Leoni, C. A. Dinarello, G. Girolomoni, et al. Blocking TH17-polarizing cytokines by histone deacetylase inhibitors in vitro and in vivo J. Leukoc. Biol., December 1, 2008; 84(6): 1540 - 1548. [Abstract] [Full Text] [PDF]